1. Introduction
All chemical transformations pass through an unstable structure called the transition state, which is poised between the chemical structures of the substrates and products. The transition states for chemical reactions are proposed to have lifetimes near 10-13 sec, the time for a single bond vibration. Thus, the transition state is the critical configuration of a reaction system situated at the highest point of the most favorable reaction path on the potential-energy surface, with its characteristics governing the dynamic behavior of reacting systems decisively. It is used primarily to understand qualitatively how chemical reactions take place.
Yet transition state structure is crucial to understanding enzymatic catalysis, because enzymes function by lowering activation energy. Linus Pauling coiled an accepted view, that incredible catalytic rate enhancements caused by enzyme is governed by tight binding to the unstable transition state structure in 1948. Because reaction rate is proportional to the fraction of the reactant in the transition state complex, the enzyme was proposed to increase the concentration of these reactive species. This proposal was further formalized by Wolfenden (1972) and coworkers, who hypothesized that the rate increase imposed by enzymes is proportional to the affinity of the enzyme to the transition state structure relative to the Michaelis complex.
Transition state structures of enzymatic targets for cancer, autoimmunity, malaria and bacterial antibiotics have been explored by the systematic application of kinetic isotope effects and computational chemistry. Today the combination of experimental and computational access to transition-state information permits the design of transition-state analogs as powerful enzymatic inhibitors and exploration of protein features linked to transition-state structure.
Molecular electrostatic potential maps of transition states serve as blueprints to guide synthesis of transition state analogue inhibitors of chosen enzymes. Substances, that ideally mimic geometric and electrostatic features of a transition state (or other intermediates of high energy) are considered as excellent enzyme inhibitors (Fig.1). They bind up to 108 times tighter than substrate. Thus, the goal of transition-state analogs design is to create stable chemical structures with van der Waals geometry and molecular electrostatic potential surfaces as close as possible to those of the transition state.
Although some reviews on the subject have been published, this concept has not been reviewed in detail [Wolfenden, 1999; Robertson, 2005; Schramm, 2005; Schramm, 2007; Dybała-Defratyka et al. 2008; Schramm, 2011]. In this review the current trends, alongside with appropriate case studies in designing of such inhibitors will be presented.
2. Choice of the target enzyme
The sequencing of the human genome has promised a revolution in medicine. The genome encodes 20,000- 25,000 human genes, and thousands more proteins as a result of alternative gene splicing. Many of these hold the keys to treating disease, especially numerous enzymes of undefined so far physiologic functions [Gonzaga-Jagureui et al., 2012]. Out of 1200 registered drugs over 300 act as enzyme inhibitors. Most of them are simple analogs of substrates of certain enzymatic reaction. Analogy to transition state as a mean to obtain effective inhibitors emerged in 1970s [Lienhard, 1973]. Through the 1970s and 1980s, most of the known examples were natural products [Wolfenden, 1976]. The situation has changed in 1990s when synthetic inhibitors became the predominate examples of transition-state inhibitors. In 1995, there were transition-state analogues for at least 130 enzymes [Radzicka & Wolfenden, 1995].
The design of transition-state inhibitors is likely to become more frequent in the future, alongside with the development of theory and technology for understanding enzyme transition states. Today the sequence of information required to obtain transition state analog of enzymatic reaction considers: choice of the suitable enzyme (most likely suited to kinetic isotope effect measurement), selection of presumable mechanism(s) of catalyzed reaction, measurement of kinetic isotope effects (KIE), computer-aided calculations matching the intrinsic KIEs, construction of steric and electronic map of transition state and synthesis of stable compound(s) matching this map [Schramm, 2007]. This procedure has been developed gradually in parallel with the advances in KIE enzymology, computational chemistry, and synthetic organic chemistry.
3. Determination of transition state architecture
At present, the most reliable method to determine three-dimensional architecture of transition state is through the use of computational methods in conjunction with experimentally measured kinetic isotope effect (KIE).
Isotopic substitution is a useful technique for probing reaction mechanisms. The change of an isotope may affect the reaction rate in a number of ways, providing clues to the pathway of the reaction. The advantage of isotopic substitution is that this is the least disturbing structural change that can be effected in a molecule. Replacement of one isotope of the substrate by another at vicinity where bonds are being or re-hybridizing typically leads to a change in the rate of the reaction. Thus, kinetic isotope effects measurements compare kcat/KM values between isotope-labeled and natural abundance reactants. This provides information about which bonds are broken or formed, and identifies changes in hybridization that occur during the rate limiting step of a reaction. It is reached by conversion of atom-by-atom KIE values to a specific static model with fixed bond angles and lengths by computational matching to a quantum chemical model of the reaction of interest. Substrate, intermediate and product geometries are located as the global minima. Transition-state structures are located with a single imaginary frequency, characteristic of true potential energy saddle points.
Such an analysis was performed recently for human thymidine phosphorylase, an enzyme responsible for thymidine homeostasis, action of which promotes angiogenesis. Thus, inhibitors of this enzyme might be considered as promising anticancer agents. Its transition state was characterized using multiple kinetic isotope effect measurements applying isotopically (3H, 14C and 15N) enriched thymidines, which were synthesized enzymatically [Schwartz et al, 2010]. A transition state constrained to match the intrinsic KIEs was found using density functional theory. In the proposed mechanism (Fig.2), departure of the thymine results in a discrete ribocation intermediate. Thymine likely leaves deprotonated at N1 and undergoes enzyme-catalyzed protonation before the next step. In the following step, the intermediate undergoes nucleophilic attack from an activated water molecule to form the products. The latter step is a reaction rate limiting step as determined by energetics of its transition state. The transition state model predicts that deoxyribose adopts a mild 3′-
Such studies, although cumbersome and difficult, are being recently more and more popular, as demonstrated by representative studies on
Computational chemistry provides techniques for the generation and exploration of the multi-dimensional energy surfaces that govern chemical reactivity. Therefore, energy minima and saddle points can be located and characterized. The pathways that interconnect them can be determined. Thus, computational methods are increasingly at the forefront of elucidating mechanisms of enzyme-catalyzed reactions, and shedding light on the determinants of specificity and efficiency of catalysis [Kollman et al., 2002; Parks et al., 2010; Williams, 2010; Lonsdake et al., 2012].
At the beginning of a molecular modeling study choice upon the specific catalytic process to model has to be undertaken. This decision may sound simple, but it includes the nontrivial task of exhaustively searching the literature to determine what is already known about the selected enzymatic system, either from experiments or from previous computational studies. Reaction mechanisms may have already been proposed in the literature, and thus provide a logical starting point for modeling studies. The three-dimensional structure of the enzyme, preferably with a bound substrate analog, reaction product or inhibitor, is among the most critical sources of information. In practice, this usually means that a high-resolution X-ray crystal structure of a reacting enzyme complex is required.
Molecular mechanics methods are important in simulations of enzymes, even though these methods cannot model chemical reactions. For that molecular dynamics simulations, or combination of molecular mechanics with quantum mechanical methods are commonly used [Senn & Thiel, 2007; Hou & Cui, 2011; Kosugi & Hayashi, 2012; Londsdale et al., 2012]. Enzymes are large molecules consisting of thousands of atoms whereas the active site may comprise only around 100 atoms. Since quantum chemical calculations are nowadays affordable only for up to a few hundred atoms (depending on the level of accuracy) the system is split into two regions: a small region encapsulating the reaction at the active site is modeled with a quantum mechanical methods, while the rest of the enzyme alongside with surrounding water is modeled using molecular mechanics (Fig. 3.)
These calculations do not take in the consideration such an important factor as protein dynamic. There is an agreement that fast (at nano- or picosecond scale) protein motions couple directly to transition state formation in enzymatically catalyzed reactions and are an integral part of the reaction coordinate. Slower protein dynamic motions also influence the heights of barriers in enzymatic reactions, however detailed description of these effects require elaboration of new computational methods [Saen-oon et al., 2008].
4. Inhibitors of proteinases
First inhibitors being transition state analogs were designed for proteolytic enzymes. The design was based on the resemblance of transition state of phosphonamidates and phosphonic, phosphinic (Fig. 4) acids to the sp3 intermediate of the hydrolysis of peptide bond. Because the lengths of oxygen-to-phosphorus and carbon-to-phosphorus bonds are significantly longer than the corresponding carbon-to-carbon and carbon-to-oxygen bonds, organophosphorus fragment of the molecule might be considered as “swollen” tetrahedral intermediate and thus can be treated similar to the transition state of this reaction.
Crystallography of enzyme-inhibitor complexes and molecular modeling studies had shown that their potent inhibitory activities result from both: resemblance to the transition state and strong electrostatic interactions between positively charged active-site metal ions (predominantly zinc ions) and negatively charged phosphonic acid (or related) group [Mucha et al., 2010; Mucha et al., 2011]. Although the phosphonate/phosphinate group is a rather weak zinc complexing moiety, it offers other advantageous structural and electronic features [Collinsova & Jiráček, 2000].
Simple phosphonic acid analogs of amino acids and pseudopeptides, containing phosphinate moiety replacing scissile peptide bond, are acting via this mechanism and rank amongst most potent inhibitors of metalloproteinases (Fig. 5). Inhibitors of neutral alanyl (M1) and leucine (M17) aminopeptidases are among the most recognized and most intensively studied representatives of metal-containing exopeptidases of biomedical significance [Lowther & Matthews, 2002; Grembecka et al., 2003; Vassiliou et. al. 2007]. Functions related to tumorigenesis and invasion makes these enzymes molecular targets for the development of potential anticancer drugs [Grembecka & Kafarski, 2001; Zhang & Xu, 2008; Fournié-Zaluski et al., 2009; Grzywa et al., 2010]. The recognized role of neutral aminopeptidase in the pathogenesis of hypertension provides also an opportunity for regulating arterial blood pressure by their inhibitors [Banegas et al., 2006; Bodineau et al., 2008]. Additionally, two of these pseudodipeptides appear to be excellent inhibitors when applied to
The design and development of pseudopeptidic inhibitors of aminopeptidases are greatly facilitated by two factors. First, the results of extensive structure-activity relationship studies, available for a wide collection of fluorogenic substrates, have defined the requirements of the S1 binding pockets of these enzymes [Drag & Salvesen, 2009; Drag et al., 2010; Gajda et al., 2012; Poręba et al., 2011; Poręba 2012]. Second, computer-aided analysis of numerous crystal structures available for leucine aminopeptidase has pointed to this enzyme as a primary molecular target for extending and optimizing interactions within the S1’ pocket [Grembecka et al., 2001; Jørgensen et al., 2002; Evdokimov et al., 2007; Khandelwal et al., 2005; Khaliullin et al. 2010; Li et al., 2010].
Phosphinic pseudopeptides have also clearly revealed their potential for the regulation of matrix metalloproteinases (MMPs, matrixins), zinc-dependent endopeptidases implicated in the breakdown of the extracellular matrix [Yiotakis at al., 2004; Fisher & Mobashery, 2006]. Cleavage of the matrix component (collagen, lamanin, elastin, gelatin, etc.) is physiologically essential for tissue remodeling processes such as morphogenesis, embryogenesis and reproduction [Overall & Kleifield, 2006; Sang et. al., 2006]. Overexpression or inadequate level of matrix metalloproteinases leads to pathological states such as osteoarthritis, rheumatoid arthritis and inflammation, but it is most associated with tumor growth, invasion, and metastasis. Angiogenetic process favored by these enzymes is essential for vascoularization and growth of tumors. Thus, they were the first proteinase targets seriously considered for combating cancer. Despite that preliminary clinical/preclinical studies on MMP inhibition in tumor models brought positive results the outcome in the drug market has been so far unsatisfactory. The spectacular failure of the last-step clinical trials is mainly due to a lack of selectivity and serious side effects [Fisher & Mobashery, 2006]. The field is now resurging with careful reinvestigation of the precise roles of each particular MMP member and a focus on the development of selective inhibitors that fully discriminate between different members of the MMP family [Reiter et al., 2003; Matziari et al., 2007; Zucker & Cao, 2009; Devel et al., 2010; Johnson et al., 2011]. Such selectivity had been reached by variation of peptide scaffold by means of combinatorial pseudopeptide synthesis [Buchardt et al, 2000; Dive et al., 2004] or by application of molecular modeling based on crystallographic studies of these enzymes [Rao, 2005; Pirard, 2007; Verma & Hansch, 2007; Anzellotti & Farrell, 2008; Kalva et al., 2012]. Representative selective inhibitors of this class are shown in Figure 6.
Quite interesting approach is preparation of hybrid systems as this composed of a phosphinate transition state analogue that has been incorporated within a triple-helical peptide template. The template sequence was based on the α1(V)436-450 collagen region, which is hydrolyzed at the Gly439-Val440 bond selectively by MMP-2 and MMP-9. In that manner highly selective inhibitor towards these two gelatinases was found [Lauer-Fields et al., 2007; Lauer-Fields et al., 2008].
Phosphinic transition state analog approach has been also recently applied for the design and synthesis of novel potent inhibitors of other proteinases of medicinal importance. Thus, inhibitors of angiotensin converting enzyme [Mores et al., 2008; Julien et al. 2010; Akif et al., 2011] are potential drugs against hypertension, aspartyl aminopeptidase as antimalarial agent [Teuscher et al., 2007], inhibitors of cathepsin C and renal dipeptidase may be considered as potential anticancer agents [Gurulingappa et al., 2003: Mucha et al., 2004], inhibitors of sortase, which is bacterial virulence protein [Kruger et al., 2004], whereas inhibition of pyroglutamyl peptidase II enhances the analeptic effect of thyrotropin [Matziari et al., 2008; Lazcano et al. 2012].
It is worth mentioning that
Sulfonamides also mimic both shape and electronic environment of the transition state of peptide bond hydrolysis. This approach was used for introduction of transition state inhibitors of HIV-protease, thermolysin and thrombine as well as haptens for generation of catalytic antibodies (Fig. 8) [Moree, et al., 1993; Moree, et al., 1995; Löwik et al., 2000; Liskamp & Kruijzer, 2004; Turcotte et al., 2012]. Unfortunately most of them appeared to be ineffective. This might be explained by non-typical bonding of potent inhibitor of this class with HIV protease (Fig. 9). It appeared that sulfonamide moiety displaces water molecule from active site and forms hydrogen bonds with two isoleucines, not as expected with catalytic aspartic acids [Meanwell, 2011]. Thus, sulfonamide group does not act as transition state analogue.
Begacestat (Fig. 8), an effective and potent inhibitor of γ-secretase is an exception here [Mayer et al., 2008; Martone et al., 2009]. γ-Secretase catalyzes the final step in the generation of amyloid β peptides from amyloid precursor protein. Amyloid β-peptides aggregate to form neurotoxic oligomers, senile plaques, and congophilic angiopathy, some of the cardinal pathologies associated with Alzheimer's disease. Begacestat appeared to be well tolerated in mouse and dog toxicity studies and has been advanced to human clinical trials for the treatment of this neurological disease.
Dialkylsilanediols are tetrahedral functional groups that can mimic hydrated carbonyls and thus might be also considered as „swollen“ intermediates of peptide bond hydrolysis. When silanediols are embedded in a peptide-like structure, they are recognized by proteinases and act as hydrolytically stable entities. Thus, dialkylsilanol is an effective functional group for the design of active site-directed protease inhibitors. This concept has been successfully tested by replacing the presumed tetrahedral carbon of thermolysin, HIV-protease and angiotensin converting enzyme substrates with silanediol groups (Fig. 10), which resulted in potent inhibitors of these enzymes [Juers et al., 2005; Sieburth & Chen, 2006; Bo et al., 2011; Meanwell, 2011].
5. Hydroxyethylene intermediate analogs as inhibitors of proteases
Aspartic proteases generally bind 6-10 amino acid regions of their polypeptide substrates, which are typically processed with the aid of two catalytic aspartic acid residues in the active site. Thus, there is usually considerable scope for building inhibitor specificity for a particular aspartic protease by taking advantage of the collective interactions between a putative inhibitor on both sides of its scissile amide bond, and a substantial portion of the substrate-binding groove of the enzyme [Eder et al., 2007]. A very effective group of their inhibitors are simple hydroxyethylene analogs of tetrahedral oxyanion intermediates of the hydrolysis of peptide bonds. This approach is based on the structure of bestatin, a general inhibitor of aminopeptidases and aspartyl proteinases isolated in 1976 from
Today, HIV protease inhibitors constitute around 40% of available drugs against HIV. Nearly all of them contain hydroxyethylene unit as transition state analog mimic, to mention only Darunavir, Atazanavir, Fosamprenavir, Lopinavir (or Ritonavir) or the oldest one Saquinavir (Fig. 11) [Brik & Wong, 2003; Pokorna et. al, 2009].
Availability of anti-HIV drugs enabled to introduce highly active antiretroviral therapy (HAART), which resulted in dramatic decrease of the mortality and morbidity for a wide variety of opportunistic viral, bacterial, fungal and parasitic infections among HIV-infected individuals in economically developed countries [Andreoni & Perno, 2012]. Thus, the design, development and clinical success of HIV protease inhibitors represent one of the most remarkable achievements of molecular medicine. However, both the academias, as well as, the industry need to continue in their effort to develop novel, more potent compounds. This is mainly connected with HIV drug resistance, which in turn results from the high mutation rate, caused by the lack of proofreading activity of the viral reverse transcriptase. The pattern of mutations associated with the viral resistance is extremely complex as shown in Figure 12 [Pokorna et al., 2009]. Taken together, in spite of the indisputable success of the HAART and benefit to patients, new approaches to the antiviral treatment are highly desirable [Clarke, 2007; Adachi et al., 2009; Pokorna et al., 2009; Alfonso & Mozote, 2011].
Quite interestingly, small modifications of core structure of the inhibitor results in minute changes in inhibitor affinity to HIV protease as demonstrated in Figure 13 [Wu et al., 2008; Mahalingham et al., 2010].
Studies conducted in order to evaluate the influence of these antiviral drugs on the development of parasites, which are known to co-infect HIV-positive individuals, surprisingly shown, that these drugs exhibit marked antiprotozoal activity. For example Saquinavir, Lopinavir, Indinavir directly inhibited the grown of
More than 25 million people are suffering from dementia, and the annual socioeconomic worldwide costs have been estimated to exceed U.S. $200 billion. γ-Secretase, along with β -secretase produces the amyloid β-protein of Alzheimer’s disease. Because of its key role in the pathogenesis γ-secretase has been a prime target for drug discovery, and many inhibitors of this protease have been developed. These enzymes are also effectively inhibited by peptidomimetics containing hydroxyethylene fragment replacing hydrolyzed peptide bond. Only one drug (Semagacestat, Fig. 14) reached phase III clinical studies so far, however, uncovered evidence of cognitive worsening in treated patients compared with placebo led to suspension of the trials in 2010. Anyway, design, synthesis and evaluation of new low-molecular, nanomolar inhibitors of secretases, structure of which significantly drifted away from peptidic transition state analogs (Fig. 14), is still challenging and brought new promising results [Osterman et al., 2006; Wolfe, 2012]. Due to rapid technological progress in chemistry, bioinformatics, structural biology and computer technology, computer-aided drug design plays more and more important role in this respect [Avram et al., 2006; Fujimoto et al., 2008; Xu et al., 2009; Al-Tel et al. 2011; Hamada et al., 2012].
Hypertension is a major risk factor for cardiovascular diseases such as stroke, myocardial infarction, and heart failure, the leading causes of death in the Western world. Inhibitors of the renin–angiotensin system have proven to be successful treatments for hypertension. As renin specifically catalyses the rate limiting step of this system, it represents the optimal target for antihypertensive drugs. Aliskiren (Fig. 15), a promising drug lowering blood pressure in sodium-depleted marmosets and hypertensive human patients, was developed using a combination of crystal structure analysis of renin–inhibitor complexes and computational methods [Wood et al., 2003]. The therapy was introduced under the names Takturna and Rasilez.
Another possibility arose from use of fluoroketone derivatives. α-monofluoroketones are approximately 50% hydrated, whereas the α,α-difluoroketones are 100% hydrated in aqueous solutions (Fig. 16). The latter ones are obviously of choice because of their striking similarity to phosphinic inhibitors (two hydroxyls placed at terahedral atom). This approach is applied very rarely but gave good inhibitors of fungal endothiapepsin [Tuan et al., 2007] and matrix metalloprotease [Reiter et al., 2000] (Fig. 16).
6. Suicide substrates yielding transition state analogues
Peptide aldehydes and boronic acids are inhibitors of serine and threonine enzymes forming both, hydrogen and covalent bonds in the enzyme active site. Tetrahedral adduct generated from these compounds upon their action on enzymes bear a closer relationship to the structure of the true intermediate and they may be considered as suicidal substrates. There is, however, an important difference between these two types of inhibitors. The boronic acid derivative possesses a negative charge, whereas the hemiacetal adduct is neutral (Fig 17).
Hence, the peptidyl boronic acid adduct is a better transition state analog than the hemiacetal formed from peptidic aldehyde [Polgár, 2005]. Aldehydes typically have a low prevalence in drugs and drug candidates because of their potential chemical reactivity and susceptibility to be engaged in a reduction/oxidation pathways in vivo. Therefore peptidyl boronic acids are considered as far better drug candidates. Additionally slight changes in pH can result in release of the inhibitor from the active site, which is profitous.
In 2003, bortezomib (Fig. 18), a first-in-class therapeutic, gained approval from the US Federal Drug Administration for the treatment of relapsed multiple myeloma and mantle cell lymphoma. Approval in the UK, for multiple myeloma, followed in 2006. It possesses a unique mode of action. Bortezomib acts as inhibitor of the 26S proteasome, the key regulator of intracellular protein degradation, found in the nucleus and cytosol of all eukaryotic cells, and forming part of the critical ubiquitin-proteasome system. This inhibition results in disruption of homeostatic mechanisms within the cell that can lead to cell death.
This finding initiated intensive researches on boronic inhibitors of serine and threonine proteases [Trippier & McGuigan, 2010]. For, example recently inhibitors of Lon proteases (bacterial ATP-dependent protease conferring bacterial virulence) afforded interesting antibacterial agents [Frase and Lee, 2007], inhibitors of prostate-specific antigen for prostate cancer imaging and therapy [LeBeau et al., 2008], antifungal inhibitors of kexin (regulatory proteins from
7. Other hydrolases
The data considering transition state analogue inhibitors of other hydrolases are practically limited to inhibitors of β–lactamases, arginase and urease.
Antibiotic resistance, especially to widely prescribed β-lactam antibiotics, is a serious threat to public health and is responsible for the increase in morbidity, mortality, and health care costs related to the treatment of bacterial infections. In most cases emergence of antibiotic-resistant bacteria is primarily driven by overuse of β-lactam antibiotics in food and agricultural products. The most prominent resistance mechanism is related to the expression of β-lactamases, which hydrolyze β–lactam fragment of the drug molecule. In nature, four classes of these enzymes exist. Three of them are serine-based, whereas fourth is zinc-dependent-hydrolase. To counteract β-lactamases, mechanism-based inhibitors were developed to be administered in concert with β-lactam antibiotics. Presently, there are three commercially available β-lactamase inhibitors (clavulanate, sulbactam, and tazobactam). The new approach to obtain such inhibitors is combination of structure of potent β-lactam antibiotics with a boronic [Thomson, et al., 2007; Eidam et al., 2010: Ke, et al., 2011; Chan, et al., 2012] or phosphonic [Nukaga, et al., 2004] acid moieties with the goal of mimicking the transition state and creating a high-affinity, reversible inhibitor that cannot be inactivated by β-lactamases since they do not bear hydrolyzable β-lactam ring.
Arginase is a binuclear manganese metalloenzyme that serves as a therapeutic target for the treatment of asthma, erectile dysfunction, and atherosclerosis. The hydrolysis of
Urease catalyzes hydrolysis of urea in the last step of organic nitrogen mineralization to give ammonia and carbamate, which decomposes to give a second molecule of ammonia and bicarbonate (Fig. 22). The hydrolysis of the reaction products induces an overall pH increase that has negative implications both in human and animal health as well as in the ecosphere. Urease is a virulence factor in infections of urinary (
Recently design, synthesis, and evaluation of novel ogranophosphonate inhibitors of bacterial urease have been described as an attractive alternative to known phosphoramidates. On the basis of the crystal structure of
8. Peptide bond formation by ribosome
Ribosomes are molecular machines that synthesize proteins in the cell. Recent biochemical analyses and high-resolution crystal structures of the bacterial ribosome have shown that the active site for the formation of peptide bonds – the peptidyl-transferase center – is composed solely of rRNA. Thus, the ribosome is the largest known RNA catalyst and the only natural ribozyme that has a synthetic activity. Peptide bond formation during ribosomal protein synthesis involves an aminolysis reaction between the aminoacyl α-amino group and the carbonyl ester of the growing peptide via a transition state with a developing negative charge - the oxyanion. Therefore the observed intermediates and transition states are similar to those observed in proteinases (Fig. 23). Structural and molecular dynamic studies have suggested that the ribosome may stabilize the oxyanion in the transition state of peptide bond formation via a highly ordered water molecule [Rodnina et al., 2006; Carrasco et al., 2011].
To biochemically elucidate how the ribosome stabilizes the developing negative charge in the transition state of peptide bond formation, a series of tetrahedral transition state mimics were synthesized. Their relative binding affinities for the ribosomes also were measured (Fig. 23). The obtained results confirmed high affinity of predicted mechanism of ribosome action [Green & Lorsch, 2002; Weinger et al., 2004; Carrasco, et al., 2011].
9. Enzymes forming amide and ester bonds via carboxylic-phosphate anhydride
Activation of carboxylic group of amino acid by ATP-phosphorylation yielding mixed carboxylic-phosphate anhydride is quite popular mechanism of synthesis of amide and ester bonds.
Similarly acting inhibitors have been found for glutamine synthetase (phosphinothricin and methionine sulfoximine and their analogs) [Berlicki et al., 2005; Berlicki & Kafarski 2006; Berlicki, 2008], γ-glutamylcysteine synthetase [Hibi et al., 2004], or penicillin binding proteins [Dzekieva et al., 2010; Dzekieva et al., 2012] (Fig. 25).
10. Nucleotide deaminases
Enzymes of the deaminase superfamily catalyze deamination of bases in nucleotides and nucleic acids across in diverse biological contexts. Representatives that act on free nucleotides or bases are primarily involved in the salvage of pyrimidines and purines, or in their catabolism in bacteria, eukaryotes and phages. Other members of the deaminase superfamily catalyze the
Adenosine deaminase (ADA) is an enzyme present in all organisms and catalyzes the irreversible deamination of adenosine and deoxyadenosine to inosine and deoxyinosine (Fig. 26). Both adenosine and deoxyadenosine are biologically active purines that can have a deep impact on cellular physiology. For example it plays a vital role in regulating T-cell coactivation. Deficiency of this enzyme in humans causes severe combined immunodeficiency. Increased serum activity of this enzyme have been found in many infectious diseases caused by microorganisms infecting the macrophages, in leprosy, brucellosis, HIV infections, viral hepatitis, infectious mononucleosis, liver cirrhosis and tuberculosis. Its extended transition state inhibitor – conformycin was isolated from
The wide potential of these inhibitors may be illustrated by the fact that deaminoformycin was recently applied to evaluate mechanisms responsible for lethality caused by genetic and herbicide-based activity of adenosine deaminase [Sabina et al., 2007], as well as identification of highly selective inhibitor of purine salvage pathway in malaria parasites [Tyler et al., 2007]. This is because of a unique feature of
Guanine deaminase is an enzyme that hydrolyzes guanine to form xanthine that is unsuitable for DNA/RNA buildup. This enzyme has been found in normal or transformed human organs and sera. One of the approaches for antiviral/anticancer therapy is to design structural mimics of natural guanine as nucleic acid building blocks, with an anticipation that such analogs would be incorporated into DNA/RNA of virus for cancer cells, interrupting their normal replicative processes. Unfortunately these potent anticancer mimics are believed to be substrates for the enzyme guanine deaminase, which converts them into their respective inactive forms. A potent inhibitor would restore the original potency of these anticancer compounds. Such an activity was determined for azepinomycin [Isshiki et al., 1987] and its analog designed as transition state of this reaction (Fig. 27) [Chakraborty et al., 2011].
11. Glycosidases and related enzymes
Glycoside hydrolases, the enzymes catalyzing hydrolysis of the glycosidic bond in di-, oligo- and polysaccharides, and glycoconjugates, are ubiquitous in Nature and fundamental to existence. The extreme stability of the glycosidic bond caused that they have evolved into highly proficient catalysts, with an estimated 1017 fold rate enhancement over the uncatalysed reaction. Such rate enhancements mean that enzymes bind the substrate at the transition state with extraordinary affinity [Gloster & Davies, 2010].
In the most cases of glycoside hydrolysis, the short-lived transition state possesses substantial oxocarbenium character (Fig. 27) resembling classical SN1 reaction intermediate. Under these conditions the anomeric carbon possesses trigonal character, which causes sp2 hybridisation predominantly along the bond between the anomeric carbon and endocyclic oxygen and significant relative positive charge accumulation on the pyranose ring [Lee et al., 2004; Biarnés et al., 2011; Davies at al., 2012].
The quest for potent and selective inhibitors of glycosidases is extremely active at present. This results from the involvement of glycosidases in lysosomal storage disorders, cancer, viral infections, diabetes and many others. Consequently a plethora of glycosidase inhibitors have been already synthesized and evaluated. The number of them is continually growing. It is outside the scope of this chapter to mention all of them in detail. One of the most appealing ways to design a transition state analog would be to incorporate both the features of geometry and charge present at the transition state. Distortion of the ring to generate compounds which may resemble the geometry of the transition state can be done by introducing a double bond in the pseudo-glycoside ring itself, whereas introduction of the charge might be done by application of sulfonium or ammonium ions [Rempel & Withers, 2008; Gloster & Davies, 2010; Sumida et al., 2012].
Some representatives, which fulfills these requirements are: salicinol, one of the active principles in the aqueous extracts of
Sialic acids play an important role in a variety of biological processes. They are usually attached to the terminal positions of glycoproteins, glycolipids and oligosaccharides. From more than 100 different sialic acids,
Influenza viruses, in particular those of type A that can infect animals and humans, continue to represent a major threat to public health and animal health worldwide. The social and economic burden associated with a pandemic is substantial. Two viral surface glycoproteins, the sialoside-hydrolysing neuraminidase and the sialic acid-binding hemagglutinin, have become important targets for such approach. Most likely, the function of flu virus neuraminidase is to remove sialic acid receptors for the virus from the host cells, and also, perhaps more importantly, from the newly formed virus particles themselves [Nelson & Holmes, 2007; Medina & Garcia-Sastre, 2011]. Three inhibitors of neuraminidase have been successfully introduced as anti-influenza drugs, all of them being transition state analog inhibitors. They were designed by systematic reduction of DANA structure using crystallographic data and computer-aided methods [Wei, et al., 2006]. Relenza (zanamivir) was the first inhibitor to be synthesized which specifically inhibited neuraminidases of both Type A and Type B influenza viruses and is effective in controlling influenza infections. In people is given as a powder by oral inhalation [Palese et al., 1974]. Interestingly, it is weaker inhibitor of neuramidase than DANA, however, DANA inhibited influenza virus replication in tissue culture but failed to prevent disease in flu-infected animals. In order to produce a neuraminidase inhibitor, which was orally bioavailable and which was taken orally in capsules or as a suspension, Tamiflu (oseltavimir) was developed in 1997 [Kim et al.]. Third drug, which has been authorized for the emergency use of treatment of certain hospitalized patients with known or suspected 2009 H1N1 influenza, is permavir [Chand, et al., 2005]. Structures of these drugs are presented in Figure 30.
All three drugs soon became lead structures for the design and preparation of new, presumably more effective ones. Syntheses and eveluation of phosphinic analogs and significantly simplified analogs of permavir (Fig. 31) have been recently described [Kati et al., 2001; Bianco et al., 2005; Shie et al., 2007; Udommaneethanakit et al., 2009].
Modified phosphonic analogs of oseltamivir were used to functionalize gold nanoparticles and were found to bind strongly and selectively to all seasonal and pandemic influenza virus strains, and thus could serve as prototypes for novel virus sensors. This may be helpul in fast influenza diagnosis [Stanley et al., 2012].
12. Transition state analogues of nucleic acids metabolism
The focus on transition states for a family of
Newborns with a genetic deficiency of purine nucleoside phosphorylase are normal, but exhibit a specific T-cell immunodeficiency during the first years of development. All other cell and organ systems remain functional. Human purine nucleoside phosphorylase degrades deoxyguanosine, and apoptosis of T-cells occurs as a consequence of the accumulation of deoxyguanosine in the circulation. Thus, control of T-cell proliferation is desirable in T-cell cancers, autoimmune diseases, and tissue transplant rejection. The search for powerful inhibitors of these enzymes as anti-T-cell agents has culminated in the discovery of immucillins. The atomic replacements between inosine and immunocilin H make an insignificant change in atomic size, but a dramatic change in the molecular electrostatic potential surface (Fig. 33). Thus, analysis of the molecular electrostatic potential surface similarity between transition state and immucilin confirmed utility of this simple approach in helping to design effective inhibitor [Schramm, 2002; Schramm, 2007].
Evolution of immucilin structure, performed using standard structural analogy techniques, enabled to obtain new inhibitors of purine nucleotide phosphorylase of nano- to picomolar affinities to the enzyme (Fig. 34) [Evans et al., 2008; Edwards et al., 2009; Ho et al. 2010; Rejman et al., 2012].
Therefore, effective inhibitors of both enzymes influence the life cycle of P. falciparum and these pathways have been targets for antimalarials since the discovery that
Immunocillins HP and GP [Shi et al., 1999] and BCX4945 [Cassera et al., 2011] (Fig. 35) appear to be effective inhibitors of phosphoribosyltransferases and are also able to influence purine nucleoside phosphorylase, being dual inhibitor of the process. Especially the efficacy, oral availability, chemical stability, unique mechanism of action and low toxicity of BCX4945 demonstrate potential for combination therapies with this novel antimalarial agent. Similar studies have been also carried out for acyclic nucleoside phosphonates [Keough et al., 2009].
Acknowledgments
This work is dedicated to Professor Henri-Jean Cristau from Ecole Nationale Superieure de Chimie in Mointpellier on the occasion of his 70th birthday.
Authors thank Polish Ministry of Science and Higher Education for financial support.
References
- 1.
Abbenante, G.; Fairlie, D. P. (2005) Protease Inhibitors in the Clinic. Medicinal Chemistry Vol. 1 (No. 1): 71-104 - 2.
Adachi, M.; Ohhara, T.; Kurihara, K.; Tamada, T.; Honjo, E.; Okazaki, N.; Arai, S.; Shoyama, Y.; Kimura, K.; Matsumura, H.; Sugiyama, S.; Adachi, H.; Takano, K.; Mori, Y.; Hidaka, K.; Kimura, T.; Hayashi, Y.; Kiso, Y. & Kuroki, R. (2009) Structure of HIV-1 Protease in Complex with Potent Inhibitor KNI-272 Determined by High-Resolution X-ray and Neutron Crystallography. Proc. Natl. Acad. Sci. U.S.A. Vol. 106 (No. 12): 4641-4646 - 3.
Akif, M.; Schwarger, S. L.; Anthony, C. S., Czrny, B.; Beau, F.; Dive, V.; Sturrock, E. D. & Acharya, D. L. (2011) Novel Mechanism of Inhibition of Human Angiotensin-I-Converting Enzyme (ACE) by a Highly Specific Phosphinic Tripeptide. Biochem. J. Vol. 436 (No. 1): 53-59 - 4.
Alfonso, Y. & Monzotte, L. (2011) HIV Protease Inhibitors: Effect on the Opportunistic Protozoan Parasites. Open Med. Chem. J. Vol. 5 (March 2011): 40-50 - 5.
Al-Tel, T. H.; Al-Qawasmeh, R. A.; Schmidt, M. F.; Al-Aboudi, A.; Rao, S. N.; Sabri, S. S. & Voelter, W. (2009) Rational Design and Synthesis of Potent Dibenzazepine Motifs as -Secretase Inhibitors. J. Med. Chem. Vol. 52 (No. 20): 6484-6488 - 6.
Al-Tel, T. H.; Samreen, M. H.; Al-Quawasmeh, R. A.; Schmidt, M. F.; El-Awadi, R.; Ardah, M.; Zaarour, R.; Rao, S. N. & El-Agnaf, O. (2011) Design, Synthesis, and Qualitative Structure-Activity Evaluations of Novel -Secretase Inhibitors as Potential Alzheimer’s Drug Leads. J. Med. Chem. Vol. 54 (No. 24): 8373-8385 - 7.
Andreoni, M. & Perno, C. F. (2012) Positioning of HIV-Protease Inhibitors in Clinical Practice. Eur. Rev. Med. Pharmacol. Sci. Vol. 16 (No. 1): 10-18 - 8.
Anzellotti, A. I., & Farrell, N. P. (2008) Zinc Metalloproteins as Medicinal Targets. Chem. Soc. Rev. Vol. 37 (No. 8): 1629-1651 - 9.
Avram, S.; Milac, A. L.; Mihailescu, D. L.; Dabu, A. & Flonta M. L. (2006) Computer-Aided Drug Design Applied to Beta and Gamma Secretase Inhibitors-Perspectives for New Alzheimer Disease Therapy. Curr. Enzyme Inhib. Vol. 2 (No. 4): 311-328 - 10.
Banegas, I.; Prieto, I; Vives, F.; Alba, F.; deGAsparo, M.; Segarra, A. B.; Hermoso, F.; Durán, R. & Ramirez, M. (2006) Brain Aminopeptidases and Hypertension. J. Renin Angiotensin Aldosterone Syst. Vol. 7 (No.3): 129-134 - 11.
Barinka, C.; Hlouchova, K.; Rovenska, M.; Majer, P.; Dauter, M.; Hin, N.; Ko, Y.-S.; Tsukamoto, T.; Slusher, B. S.; Konvalinka, J. & Lubkowski, J. (2008) Structural Basis of Interactions between Human Glutamate Carboxypeptidase II and Its Substrate Analogs. J. Mol. Biol. Vol. 376 (No. 5): 1438-1350 - 12.
Berlicki, L.; Obojska, A.; Forlani, G. & Kafarski, P. (2005) Design, Synthesis, and Activity of Analogues of Phosphinothricin as Inhibitors of Glutamine Synthetase. J. Med. Chem. Vol. 48 (No. 20): 6340-6349 - 13.
Berlicki, L. & Kafarski P. (2006) Computer-aided Analysis of the Interactions of Glutamine Synthetase with its Inhibitors. Bioorg. Med. Chem. Vol. 14 (No. 13): 4578 - 4585 - 14.
Berlicki, L. (2008) Inhibitors of Glutamine Synthetase and Their Potential Application in Medicine. Mini-reviews Med. Chem. Vol. 8 (No. 9): 869 - 878 - 15.
Berlicki, L.; Bochno, M.; Grabowiecka, A.; Białas, A.; Kosikowska, P. & Kafarski P. (2012) N-Substituted Aminomethanephosphonic and Aminomethane-P-methylphosphinic Acids as Inhibitors of Ureases. Amino Acids Vol. 42 (No. 5): 1937-1942 - 16.
Bhat, R. G.; Kumar, N. G. & Pinto, B. M. (2007) Synthesis of Phosphate Derivatives Related to the Glycosidase Inhibitor Salacinol. Glycomimetics Vol. 342 (No. 12-13): 1934-1942 - 17.
Bianco, A.; Brufani, M.; Dri, D. A.; Melchioni, C. & Filocamo, L. (2005) Design and Synthesis of a New Furanosic Sialylmimetic as a Potential Influenza Neuraminidase Viral Inhibitor. Lett. Org. Chem. Vol. 2 (No. 1): 83-89 - 18.
Biarnés, X.; Ardèvol. A.; Iglesias-Fernández, J.; Planas, A. & Rovira, C. (2011) Catalytic Itinerary in 1,3-1,4--Glucanase Unraveled by QM/MM Metadynamics. Charge Is Not Yet Fully Developed at the Oxocarbenium Ion-like Transition State. J. Am.Chem. Soc. Vol. 133 (No. 50): 20301-20309 - 19.
Bo, Y.; Singh, S.; Duong, H. Q.; Cao, C. & Sieburtf, S. McN. (2011) Efficient, Enantioselective Assembly of Silanediol Protease Inhibitors. Org. Lett. Vol. 13 (No.7): 1387-1389 - 20.
Bodineau, L.; Fugière, A.; Marc, Y.; Inguimbert, N.; Fassot, C.; Balavoine, F.; Roques, B. & Llorens-Cortes, C. (2008) Orally Active Aminopeptidase A Inhibitors Reduce Blood Pressure A New Strategy for Treating Hypertension. Hypertension Vol. 51 (No. 5): 1318-1325 - 21.
Breuer, E.; Salomon, C. J.; Katz, Y.; Chen, W.; Lu, S.; Röschenthaler, G.-V.; Hander, R. & Reich, R. (2004) Carbamoylphosphonates, a New Class of In vivo Active Matrix Metalloproteinase Inhibitors. 1. Alkyl- and Cycloalkylcarbamoylphosphonic Acids.J. Med. Chem. Vol. 47 (No. 11): 2826-2832 - 22.
Brik, A. & Wong, C.-H. (2003) HIV-1 Protease: Mechanism and Drug Discovery. Org. Biomol. Chem. Vol. 1 (No.)1: 5-14 - 23.
Buchardt, J; Bruun Schiødt, K.; Krsog-Jensen, K.; Dellaise, J.-M.; Tækker Foged, N. & Meldal, M. (2000) Solid Phase Combinatorial Library of Phosphinic Peptides for Discovery of Matrix Metalloproteinase Inhibitors. J. Comb. Chem. Vol. 2 (No. 6): 624-6238 - 24.
Cama, E.; Colleluori, D. M.; Emig, F. A.; Shin, H.; Kim, S. W.; Kim, N. N.; Traish, A. M.; Ash, D. E. & Christianson, D. W. (2003) Human Arginase II: Crystal Structure and Physiological Role in Male and Female Sexual Arousal. Biochemistry Vol. 43 (No. 28): 8445-8451 - 25.
Cama, E.; Shin, H. & Christianson, D. W. (2003a) Design of Amino Acid Sulfonamides as Transition-State Analogue Inhibitors of Arginase. J. Am. Chem. Soc. Vol. 125 (No. 43): 13052-13057 - 26.
Carrasco, N.; Hiller, D. A. & Strobel S. A. (2011) Minimal Transition State Charge Stabilization of the Oxyanion During Peptide Bond Formation by the Ribosome. Biochemistry Vol. 50 (No. 48): 10491-10498 - 27.
Cassera, M. B.; Hazleton, K. Z.; Merino, E. F.; Obladia III, N.; Ho, M.-C.; Murkin, A. S.; DePinto, R.; Gutierrez, J. A.; Almo, S. C.; Evans, G. B.; Babu, Y. S. & Schramm, V. L. (2011) Plasmodium falciparum Parasites Are Killed by a Transition State Analogue of Purine Nucleoside Phosphorylase in a Primate Animal Model, PloS ONE Vol. 6 (No. 11): e26916 - 28.
Chaerkady, R. & Sharma, K. K. (2004) Characterization of a Bradykinin-Hydrolyzing Protease from the Bovine Lens. Invest. Ophthalmol. Vis. Sci. Vol. 45 (No. 4): 1214-1223 - 29.
Chakraborty, S.; Shah, N. K.; Fishbein, J. C. & Hoschamne R. S. (2011) A Novel Transition State Analog Inhibitor of Guanase Based on Azepinomycin Ring Structure: Synthesis and Biochemical Assessment of Enzyme Inhibition. Bioorg. Med. Chem. Lett. Vol. 21 (No. 2): 756-759 - 30.
Chan, F. Y.; Neves, M. A. C.; Sun, N.; Tsang, M. W.; Leung, Y. C.; Chan. T.-H.; Abagyan, R. & Wong, K. Y. (2012) Validation of the AmpC -Lactamase Binding Site and Identificationof Inhibitors with Novel Scaffolds. J. Chem. Inf. Model. Vol. 52 (No. 5): 1367-1375 - 31.
Chand, P.; Bantia, S.; Kotian, P.; El-Kattan, Y.; Lin, T. & Babu, Y. S. (2005) Comparison of the Anti-influenza Virus Activity of Cyclopentanederivatives with Oseltamivir and Zanamivir In Vivo. Bioorg. Med. Chem. Vol. 13 (No. 12): 4071–4077. - 32.
Charrier, N.; Clarke, B.; Cutler, L.; Demont, E.; Dingwall, C.; Dunsdon, R.; East, P.; Hawkins, J,.; Howes, C.; Hussain, I.; Jeffrey, P.; Maile, G.; Matico, R.; Mosley, J.; Naylor, A.; O'Brien, A.; Redsahw, S.; Rowland, P.; Soleil, V.; Smith, K.; Sweitzer, S.; Theobald, P,; Vesey, D.; Walter, D. S. & Wayne, G. (2008) Second Generation of Hydroxyethylamine BACE-1 Inhibitors: Optimizing Potency and Oral Bioavailability. J. Med. Chem. Vol 51 (no.11): 3313-3317 - 33.
Chen, S. A.; Sieburth S. McN.; Glekas, A.; Hewitt, G. W.; Trainor, G. L.; Erickson-Viitanen, S.; Garbor, S. S.; Cordova, B.; Jeffrey, S. & Klabe, R. M. (2001) Drug Design with a New Transition State Analog of the Hydrated Carbonyl: Silicon-based Inhibitors of the HIV Protease. Chem. Biol. Vol. 8 (No.12): 1161-1166 - 34.
Clarke, S. G. (2007) HIV Protease Inhibitors and Nuclear Lamin Processing: Getting the Right Bells and Whistles. Proc. Natl. Acad. Sci. U.S.A. Vol. 104 (No. 35): 13857-13858 - 35.
Collinsova, M. & Jiráček, J. (2000) Phosphinic Acid Compounds in Biochemistry, Biology and Medicine. Curr. Med. Chem. Vol. 7 (No. 6): 629-647 - 36.
Cunningham, E.; Drąg, M.; Kafarski, P. & Bell, A. (2008) Chemical Target Validation Studies of Aminopeptidase in Malaria Parasites Using alpha-Aminoalkylphosphonate and Phosphonopeptide Inhibitors. Antimirob. Agnets Chemother. Vol. 52 (No. 9): 3221 – 3228 - 37.
Davies, G. J.; Planas, A. P. & Rovira C. (2012) Conformational Analyses of the Reaction Coordinate of Glycosidases. Acc. Chem. Res. Vol. 45 (No.2): 308-316 - 38.
Devel, L.; Garcia, S.; Czarny B.; Beau, F.; Lajeunesse, E.; Vera, L.; Georgiadis, D.; Sture , E. & Dive, V. (2010) Insights from Selective Non-phosphinic Inhibitors of MMP-12 Tailored to Fit with an S1’ Loop Canonical Conformation. J. Biol. Chem. Vol. 285 (No. 46): 35900-35909 - 39.
Dive, V.; Georgiadis, D.; Matziari, M.; Beau, F.; Cuniasse, P. & Yiotakis, A. (2004) Phosphinic Peptides as Zinc Metalloproteinase Inhibitors. Cell. Mol. Life Sci. Vol. 61 (No. 16): 2010-2019 - 40.
Drag, M. & Salvesen, G. S. (2010) Emerging Principles in Protease-based Drug Discovery. Nature Rev. Drug. Discov. Vol. 9 (September 2010): 690-701 - 41.
Drag, M.; Bogya, M.; Ellman, J. A. & Salvesen, G. S. (2010) Aminopeptidase Fingerprints, an Integrated Approach for Identification of Good Substrates and Optimal Inhibitors. J. Biol. Chem. Vol. 285 (No. 5): 3310-3318 - 42.
Dybala-Defratyka, A.; Rostkowski, M. & Paneth, P. (2008) Enzyme Mechanisms from Molecular Modeling and Isotope Effects. Archiv. Biochem. Biophys. Vol. 474 (No. 2): 274-282 - 43.
Dzekieva, L.; Rocaboy, M.; Kerff, F.; Charlier, P.; Sauvage, E. & Pratt, R. F (2010) Crystal Structure of a Complex between the Actinomadura R39 DD-Peptidase and a Peptidoglycan-mimetic Boronate Inhibitor: Interpretation of a Transition State Analogue in Terms of Catalytic Mechanism.Biochemistry Vol. 49 (No. 30): 6411-6419 - 44.
Dzekieva, L.; Kumar, I. & Pratt, R. F. (2012) Inhibition of Bacterial DD-Peptidases (Penicillin-Binding Proteins) in Membranes and in Vivo by Peptidoglycan-Mimetic Boronic Acid, Biochemistry Vol. 58 (No. 13): 2804-2811 - 45.
Eder, J.; Hommel, U.; Cumin, F.; Martoglio, B. & Gerthartz, B. (2007) Aspartic Proteases in Drug Discovery. Curr. Pharm. Des. Vol. 13 (No. 3): 271-285 - 46.
Edwards, A. A.; Mason, J. M.; Clinch, K.; Tyler, P. C.; Evans, G. B. & Schramm V. L. (2009) Altered Enthalpy-Entropy Compensation in Picomolar Transition State Analogues of Human Purine Nucleoside Phosphorylase. Biochemistry Vol. 48 (No. 23): 5226-5238 - 47.
Eidam, Oliv.; Romagnoli, C.; Caselli, E.; Babaoglu, K.; Teotico Pohlhaus, D.; Karpiak, J.; Bonnet, R.; Stoichet, B. K. & Prati, F. (2010) Design, Synthesis, Crystal Structures, and Antimicrobial Activity of Sulfonamide Boronic Acids as -Lactamase Inhibitors. J. Med. Chem. Vol. 53 (No.21): 7852-7863 - 48.
Ellsworth, B. A.; Tom, N. J. & Bartlett, P. A. (1996) Synthesis and Evaluation of Inhibitors of Bacterial D-Alanine:D-Alanine Ligases. Chem.Biol. Vol. 3, (No. 1): 37–44 - 49.
Evans, G. B.; Furneaux, R. H.; Greatrex, B.; Murkin, A. S.; Schramm, V. L. & Tyler, P. C. (2008) Azetidine Based Transition State Analogue Inhibitors of N-Ribosyl Hydrolases and Phosphorylases. J. Med.Chem. Vol. 51 (No. 4): 948-956 - 50.
Evdokimov, A. G.; Pokross, M.; Walter, R. M.; Mekel, M.; Barnett, B. L.; Amburger, J.; Seibel, W. L.; Soper, S.J.; Djung, J, F.; Fairweather, N.; Diven, C.; Rastogi, V.; Grinius, L.; Klanke, C.; Siehner, R.; Twinem, T. & Andrews, R. (2007) Serendipitous Discovery of Novel Bacterial Methionine Aminopeptidase Inhibitors. Proteins Vol. 66 (No. 3): 538-546 - 51.
Fisher, J. F. & Mobashery S. (2006) Recent Advances in Recent MMP Inhibitor Design. Cancer Matastasis Rev. Vol. 25 (No. 1): 115-136 - 52.
Fournié-Zaluski, M-.C.; Poras, H.; Roques, B.P.; Nakajima, Y.; Ito, K. & Yoshimoto, T. (2009) Structure of Aminopeptidase N from Escherichia coli Complexed with the Transition-state Analogue Aminophosphinic Inhibitor PL250.Acta Crystallogr. D Vol. 65 (No. 8): 814-822 - 53.
Frase, H. F. & Lee, I. (2007) Peptidyl Boronates Inhibit Salmonella enterica Serovar Typhimurium Lon Protease by a Competitive ATP-Dependent Mechanism,Biochemistry Vol. 46 (No.22): 6647-6657 - 54.
Fujimoto, T.; Matsushita, Y.; Gouda, H.; Yamaotsu, N. & Hirono, S. (2008) In Silico Multi-filter Screening Approaches for Developing Novel -Secretase Inhibitors. Bioorg. Med. Chem. Lett. Vol. 18 (No. 9): 2771-2775 - 55.
Gajda, A.; Pawelczak, M. & Drag, M. (2012) Substrate Specificity Screening of Oat ( Avena sativa ) Seeds Aminopeptidase Demonstrate Unusually Broad Tolerance in S1 Pocket.Plant Physiol. Biochem. Vol. 54 (May 2012): 6-9 - 56.
Ghavami, A.; Johnston, B. D. & Pinto, B. M. (2001) A New Class of Glycosidase Inhibitor: Synthesis of Salacinol and Its Stereoisomers. J. Org. Chem., Vol. 66 (No .7): 2312-2317 - 57.
Gloster, T. M. & Davies, G. J. (2010) Glycosidase Inhibition: Assessing Mimicry of the Transition State. Org. Biomol. Chem. Vol. 8 (No.): 305-320 - 58.
Gonzaga-Jagureui, C.; Lupski, J. R. & Gibbs, R. A. (2012) Human Genome Sequencing in Health and Disease. Annu. Rev. Med. Vol. 63: 35-61 - 59.
Green, R. & Lorsch, J. R. (2002) The Path to Perdition Is Paved with Protons. Cell Vol. 110 (No. 6): 665-668 - 60.
Grembecka, J. & Kafarski, P. (2001) Leucine Aminopeptidase as a Target for Inhibitor Design. Mini Rev. Med. Chem. Vol. 1 (No. 2): 133 - 144. - 61.
Grembecka, J.; Mucha, A.; Cierpicki, T. & Kafarski, P. (2003) The Most Potent Organophosphorus Inhibitors of Leucine Aminopeptidase. Structure-based Design, Chemistry, and Activity. J. Med. Chem. Vol. 46 (No. 13): 2641 – 2655 - 62.
Grzywa, R.; Oleksyszyn, J.; Salvesen, G. S. & Drag, M. (2010) Identification of Very Potent Inhibitor of Human Aminopeptidase N (CD13). Bioorg. Med. Chem. Lett. Vol. 20 (No.8): 2497-2499 - 63.
Gurulingappa, H.; Buckhaults, P.; Kumar, S. K.; Kinzler K. W.; Vogelstein, B. & Khazn, S. R. (2003) Design, Synthesis and Evaluation of New RDP Inhibitors. Tetrahedron Lett. Vol. 44 (No. 9): 1871-1873 - 64.
Hamada, Y.; Tagad, H. D.; Nishimura, Y.; Ishiura, S. & Kiso, Y. (2012) Tripeptidic BACE1 Inhibitors Devised by In-silico Conformational Structure-based Design.Bioorg. Med. Chem. Vol. 22 (No. 2): 1130-1135 - 65.
Henley, D. B.; May, P. C.; Dean, R.A. & Siemers, R. E. (2009) Development of Semagacestat (LY450139), a Functional Gamma-secretase Inhibitor, for the Treatment of Alzheimer's Disease. Expert Opinion Pharmacoother. Vol. 10 (No. 10): 1657-1654 - 66.
Hibi, T.; Nii, H.; Nakatsu, T.; Kimura, A.; Kato, H.; Hiratake, J. & Oda, J. (2004) Crystal Structure of γ -Glutamylcysteine Synthetase: Insights Into the Mechanism of Catalysis by a Key Enzyme for Glutathione Homeostasis. Proc. Natl. Acad. Sci. U.S.A. Vol. 101 (No. 42): 15052-15057 - 67.
Holyoak, T.; Kettner, C. A.; Petsko, G. A; Fuller, R. S. & Ringe, D. (2004) Structural Basis for Differences in Substrate Selectivity in Kex2 and Furin Protein Convertases. Biochemistry Vol. 43 (No. 9): 2412-2421 - 68.
Hou, G. & Cui, Q. (2011) QM/MM Analysis Suggests that Alkaline Phosphatase (AP) and Nucleotide Pyrophosphatase/Phosphodiesterase Slightly Tighten the Transition State for Phosphate Diester Hydrolysis Relative to Solution: Implication for Catalytic Promiscuity in the AP Superfamily. J. Am. Chem. Soc. Vol. 134 (No. 1): 229-246 - 69.
Hu, G.; Lin, G.; Wang, M.; Dick, L.; Xu, R. M.; Nathan, C. & Li, H. (2006) Structure of the Mycobacterium tuberculosis Proteasome and Mechanism of Inhibition by a Peptidyl Boronate. Mol. Microbiol. Vol. 59 (No. 5): 1417-1428 - 70.
Hu, Y. P; Liu, H. G.; Teng, K. H. & Liang, P. H. (2010) Mechanism of cis-Prenyltransferase Reaction Probed by Substrate Analogues. Biochem. Biophys. Res. Commun. Vol. 400 (No. 4): 758-762 - 71.
Iyer, L. M.; Zhang, D. P. ; Rogozhin, I. B. & Aravind, L. (2011) Evolution of the Deaminase Fold and Multiple Origins of Eukaryotic Editing and Mutagenic Nucleic Acid Deaminases from Bacterial Toxin Systems. Nucl. Acid. Res. Vol. 39 (No. 22): 9473-9497 - 72.
Jeurs, D. H.; Kim, J.; Matthews, B. W. & Sieburth, S. McN. (2005) Structural Analysis of Silanediols as Transition-State-Analogue Inhibitors of the Benchmark Metalloprotease Thermolysin. Biochemistry Vol. 44 (No. 50): 16524-16528 - 73.
John, S.; Thangapandian, S.; Sakkiah, S. & Lee, K. W. (2011) Potent Bace-1 Inhibitor Design Using Pharmacophore Modeling, In Silico Screening and Molecular Docking Studies. BMC Bioinformatics Vol. 12 (Suppl. 1): S28 - 74.
Johnson, J. L.; Devel, L.; Czarny, B.; George, S. J.; Jackson, C. L.; Rogakos, V.; Beau, F.; Yiokatis, A.; Newby, A. C. & Dive, V. (2011) A Selective Matrix Metalloproteinase-12 Inhibitor Retards Atherosclerotic Plaque Development in Apolipoprotein E-knockout Mice. Arterioscl. Tromb. Vasc. Biol. Vol. 31 (No. 3): 528-535 - 75.
Jørgensen, A. T.; Norrby, P. O. & Liljefors, T. (2002) Investigation of the Metal Binding Site in Methionine Aminopeptidase by Density Functional Theory. J. Comput. Aided Mol. Des. Vol. 16 (No. 3): 167-179 - 76.
Julien, N.; Makritis, A; Georgiadis, D.; Beau, F.; Yiotakis, A. & Dive, V. (2010) Phosphinic Tripeptides as Dual Angiotensin-Converting Enzyme C-Domain and Endothelin-Converting Enzyme-1 Inhibitors. J. Med. Chem,. V ol. 53 (No. 1): 208-220 - 77.
Kalva, S.; Vadivelan, S.; Sanam, R.; Jagarlapudi, S. A. R. P. & Saleena, L. M. (2012) Lead Identification and Optimization of Novel Collagenase Inhibitors; Pharmacophore and Structure Based Studies. Bioinformation Vol. 8 (No. 7): 301-308 - 78.
Kati, W. M.; Montgomery, D.; Maring, C.; Stoll, V. S.; Giranda, V.; Chen, X.; Laver, W. G.; Kohlbrenner, W. & Norbeck, D. W. (2001) Novel - and -Amino Acid Inhibitors of Influenza Virus Neuraminidase. Antimicrob. Agents Chemither. Vol. 45 (No. 9): 2563-2570 - 79.
Ke, W.; Sampson, J. M.; Ori, C.; Prato, F.; Drawz, S. E.; Bethel, C. R.; Bonomo, R. A.; & van den Akken, F. (2011) Novel Insights into the Mode of Inhibition of Class A SHV-1 -Lactamases Revealed by Boronic Acid Transition State Inhibitors. Antimicrob. Agents Chemother. Vol. 55 (No. 1): 174-183 - 80.
Keough, D. T.; Hoćkova, D.; Holy, A.; Naesenes, L. M. J.; Skinner-Adams, T. S.; de Jersey, J.; & Guddat, L. W. (2009) Inhibition of Hypoxanthine - Guanine Phosphoribosyltransferase by Acyclic Nucleoside Phosphonates:A New Class of Antimalarial Therapeutics. J. Med. Chem. Vol. 52 (No.): 4391-4399 - 81.
Khaliullin, I. G.; Suplatov, D. A.; Dalaeva, D. L.; Otsuka, M.; Asano, Y. & Švedas, V. K. (2010) Bioinformatic Analysis, Molecular Modeling of Role of Lys65 Residue in Catalytic Triad of D-aminopeptidase from Ochrobactrum anthropi. Acta Naturae Vol. 2 (No. 2): 66-71 - 82.
Khandelwal, A.; Lukacova, V.; Comez, D.; Kroll, D. M.; Raha, S. & Balaz, S. (2005) A Combination of Docking, QM/MM Methods, and MD Simulation for Binding Affinity Estimation of Metalloprotein Ligands. J. Med. Chem. Vol. 48 (No. 17): 5437-5447 - 83.
Kim, C. U.; Williams, M. A.; Lui, H.; Zhang, L.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D.B.; Tai, C. Y.; Laver, W. G. & Stevens, R. C. (1997). Influenza Neuraminidase Inhibitors Possessing a Novel Hydrophobic Interaction in the Enzyme Active Site: Design, Synthesis and Structural Analysis of Carbocyclic Sialic Acid Analogues with PotentAanti-influenza Activity. J. Am. Chem. Soc. Vol. 119 (No. 4) 681–690. - 84.
Kollman, P. A.; Kuhn, B. & Peräkylä, M. (2002) Computational Studies of Enzyme-Catalyzed Reactions: Where Are We in Predicting Mechanisms and in Understanding the Nature of Enzyme Catalysis? J. Phys. Chem. B Vol. 106 (No. 7): 1537-1542 - 85.
Kosikowska, P. & Berlicki, L. (2011) Urease Inhibitors as Potential Drugs for Gastric and Urinary Tract Infections: a Patent Review. Expert Opin. Ther. Patents Vol. 21 (No. 6): 945-957 - 86.
Kotsugi, T. & Hayashi, S. (2012) Crucial Role of Protein Flexibility in Formation of a Stable Reaction Transition State in an -Amylase Catalysis. J. Am. Chem. Soc. Vol. 134 (No. 16): 7045-7055 - 87.
Kruger, R. G.; Barkallah, S.; Frankel, B. A. & Mc Cafferty, B. G. (2004) Inhibition of the Staphylococcus aureus Sortase Transpeptidase SrtA by Phosphinic Peptidomimetics.Bioorg. Med. Chem. Vol. 12 (No.13): 3723-3729 - 88.
Lauer-Fields, J. L.; Brew, K.; Whitehead, J. K.; Li, S.; Hammer, R. P. & Fields, G.B. (2007) Triple-Helical Transition State Analogues: A New Class of Selective Matrix Metalloproteinase Inhibitors. J. Am. Chem. Soc. Vol. 129 (No. 30): 10408-10417 - 89.
Lauer-Fields, J. L.; Whitehead, J. K.; Li, S.; Hammer, R. P. ; Brew, K. & Fields, G.B. (2008) Selective Modulation of Matrix Metalloproteinase 9 (MMP-9) Functions via Exosite Inhibition. J. Biol. Chem. Vol. 283 (No.29): 20087-20095 - 90.
Lazcano, I.; Uribe, R. M.; Martinez-Cháves, E.; Vargas, M. A.; Matziari, M.; Joseph-Bravo P. & Charli, J. M. (2012) Pyroglutamyl Peptidase II Inhibition Enhances the Analeptic Effect of Thyrotropin-Releasing Hormone in the Rat Medial Septum. J. Pharmacol. Exp. Ther. Vol. 342 (No. 1): 222-231 - 91.
Lebeau, A.; Singh, P.; Isaacs, J, & Denmeade, S. R. (2008) Potent and Selective Peptidyl Boronic Acid Inhibitors of the Serine Protease Prostate-Specific Antigen. Chem. Biol. Vol. 15 (No. 7): 665-674 - 92.
Lee, J. K.; Bain, A. D. & Berti, P. J. (2004) Probing the Transition States of Four Glucoside Hydrolyses with 13C Kinetic Isotope Effects Measured at Natural Abundance by NMR Spectroscopy. J. Am. Chem. Soc. Vol. 126 (No. 12): 3769-3776 - 93.
Li, X.; Hayik, S. A. & Merz Jr, K. M. (2010) QM/MM X-Ray Refinement of Zinc Metalloenzymes. J. Inorg. Biochem. Vol. 104 (No. 5): 512-522 - 94.
Li, Y.; Cao, H.; Hai, Y.; Chen, Y.; Lau, K.; Qu, J.; Thon, V.; Sugirato, G. & Chen, X. (2011) Identifying Selective Inhibitors Against Human Cytosolic Sialidase NEU2 by Substrate Specificity Studies. Mol. Biosyst. Vol. 7 (No. 4): 1060-1072 - 95.
Lienhard, G. E. (1973) Enzymatic Catalysis and Transition-state Theory, Science Vol. 180 (No. 4082): 149-154 - 96.
Lin, Y.-L & Gao, J. (2011) Kinetic Isotope Effects of L- Dopa Decarboxylase,J. Am. Chem. Soc. Vol,. 133 (No. 12): 4398-4403 - 97.
Lipscamp, R. M. J. & Kruijtzer J. A. W. (2004) Peptide Transformation Leading to Peptide-peptidosulfonamide Hybrids and Oligo Peptidosulfonamides. Mol. Divers. Vol. 8 (No. 2): 787-97 - 98.
Liu, H.; Sim. L.; Rose, D. L. & Pinto, B. M. (2006) A New Class of Glucosidase Inhibitor: Analogues of the Naturally Occurring Glucosidase Inhibitor Salacinol with Different Ring Heteroatom Substituents and Acyclic Chain Extension. J. Org. Chem. Vol. 71 (No. 8): 3007-3013 - 99.
Lonsdale, R.; Harvey, J. N. & Mulholland, A. J. (2010) Compound I Reactivity Defines Alkene Oxidation Selectivity in Cytochrome P450cam. J. Phys. Chem. B Vol.114, (No. 2): 1156–1162 - 100.
Lonsdale, R.; Harvey, J. N. & Mulholland, A. J. (2012) A Practical Guide to Modelling Enzyme-Catalysed Reactions. Chem. Soc. Rev. Vol. 41 (No. 8): 3025–3038 - 101.
Löwik, D. W. P. M. and Liskamp, R. M. J. (2000) Synthesis of - and -Substituted Aminoethane Sulfonamide Arginine-Glycine Mimics. Eur. J.Org. Chem ., Vol. 2000 (No. 7): 1219-1228 - 102.
Lowther, W. T. & Matthews, B. W. (2002) Metalloaminopeptidases: Common Functional Themes in Disparate Structural Surroundings. Chem. Rev. Vol. 102 (No.12): 4581-4607 - 103.
Mahalingham, A. K.; Axelsson, L.; Ekegren, J. K.; Wanneberg, B.; Kihlström, J.; Unge, T,; Wallberg, H.; Samuelsson, B.; Larhed, M. & Hallberg, A (2010) HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol: Improved Antiviral Activity in Cells. J. Med. Chem. Vol. 53 (No. 2): 607-615 - 104.
Martone, R. L.; Zhou, H.; Atchison, K.; Comery, T.; Xu, J. Z.; Huang, X.; Gong, X.; Jin, M.; Kreft, A.; Harrison, B.; Mayer, S. C.; Aschmies, S.; Gonzales, C.; Zaleska, M. M.; Riddel, D. R.; Wagner, E.; Lu, P.; Sun, S.-C.; Sonnenberg-Reines, J.; Oganesian, A.; Adkins, K.; Leach, M.W.; Clarke, D. W.; Huryn, D.; Abou-Gharbia, M.; Magolda, R.; Bard, J.; Frick, G.; Raje, S.; Forlow, S. B.; Balliet, C.; Burczynski R. E.; Reinhart, P. H.; Wan, H. I.; Pangalos, M. N. & Jacobsen, J. S. (2009) Begacestat (GSI-953): A Novel, Selective Thiophene Sulfonamide Inhibitor of Amyloid Precursor Protein -Secretase for the Treatment of Alzheimer’s Disease. J. Parmacol. Exp. Ther. Vol. 331 (No. 2): 598-608 - 105.
Matziari, M.; Beau, F.; Cuniasse, P.; Dive, V. & Yiotakis, A. (2004) Evaluationof P1’-Diversified Phosphinic Peptides Leads to the Development Ofhighly Selective Inhibitors of MMP-11. J. Med. Chem. Vol. 47 (No. 2): 325-336 - 106.
Matziari, M.; Dive, V. & Yiotakis, A. (2007) Matrix Metalloproteinase 11 (MMP-11; Stromelysin-3) and Synthetic Inhibitors. Med. Res. Rev. Vol. 27 (No. 4): 528-552 - 107.
Matziari, M.; Bauer, K.; Dive, V. & Yiotakis, A. (2008) Synthesis of the Phosphinic Analogue of Thyrotropin Releasing Hormone. J. Org. Chem. Vol. 73 (No. 21): 8591-8693 - 108.
Mayer, S. C.; Kreft, A. S.; Harrison, B.; Abou-Gharbia, M.; Antane, M.; Aschmies, S.; Atchison, K.; Chlenov, M.; Cole, D. C.; Comery, T.; Diamantis, G.; Ellingboe, J.; Fan, K.; Gallante, R.; Gonzales, K.; Ho, D. M.; Hoke, M. E.; Hu, Y.; Huryn, D.; Jain, U.; Jin, M.; Kremer, K.; Kubrak, D.; Lin, M.; Lu, P.; Magolda, R.; Martone, R.; Moore, W.; Oganesian, A.; Pangalos, M. N.; Porte, A.; Reinhart, P.; Resnick, L.; Riddel, D. R.; Sonnenberg-Reines, J.; Stock, J. R.; Sun, S.-C.; Wagner, E.; Wang, T.; Woller, K.; Xu, Z.; Zaleska, M. M.; Zeldis, J.; Zhang, M.; Zhou, H. & Jacobsen J. S. (2008) Discovery of Begacestat, a Notch-1-Sparing -Secretase Inhibitor for the Treatment of Alzheimer’s Disease. J. Med. Chem. Vol. 51 (No. 23): 7348-7351 - 109.
McGowan, S.; Oellig, C. A.; Birru, W. A.; Caradoc-Davies, T. T.; Stack, C. M.; Lowther, J.; Skinner-Adams, T.; Mucha, A.; Kafarski, P.; Grembecka, J.; Trenholme, K. R.; Buckle, A. M.; Gardiner, D. L.; Dalton, J. P. & Whisstock, J. C. (2010) Structure of the Plasmodium falciparum M17 Aminopeptidase and Significance for the Design of Drugs Targeting the Neutral Exopeptidases.Proc. Natl. Acad. Sci. U.S.A. Vol. 107, (No. 6), 2449 – 2454 - 110.
McGowan, S.; Porter, C. J.; Lowther. J.; Stack, C. M.; Golding, S. J.; Skinner-Adams, T. S.; Trenholme, K. R.; Teuscher, F.; Donnelly, S. M.; Grembecka, J.; Mucha, A.; Kafarski, P.; Degori, R.; Buckle, A. M.; Gardiner, D. L.; Whisstock, J. C. & Dalton, J. P. (2009) Structural Basis for the Inhibition of the Essential Plasmodium falciparum M1 Neutral Aminopeptidase. Proc. Natl. Acad. Sci. U.S.A. Vol. 106 (No. 8): 2537 – 2542 - 111.
Medina, R. A. & Garcia-Sastre, A. (2011) Influenza A Viruses: New Research Developments. Nat. Rev. Microbiol. Vol. 9 (August 2011): 590-603 - 112.
Meanwell, N. A. (2011) Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design. J. Med. Chem. Vol. 54 (No. 8): 2529-2591 - 113.
Mohan, S. & Pinto, B. M. (2008) Zwitterionic Glycosidase Inhibitors: Salacinol and Related Analogues. Carbohydr. Res. Vol. 342 (No. 12-13): 1551-1580 - 114.
Moree, W. J.; Van Gent, L. C.; Van Der Marel, G. A. & Liskamp,R. M. J., (1993) Synthesis of Peptides Containing a Sulfinamide or a Sulfonamidetransition State Isostere. Tetrahedron Vol. 49 (No.5): 1133-1150 - 115.
Moree, W. J.; Van Der Marel, G. A. & Liskamp, R. M. J. (1995) Synthesis of Peptidosulfinamides and Peptidosulfonamides Containing the Sulfinamide or Sulfonamide Transition-state Isostere. J. Org. Chem ., Vol. 60 (No. 16): 5157-5169 - 116.
Mores, A.; Matziari, M.; Beau, F.; Cuniasse, P.; Yiotakis, A. & Dive, V,.(2008) Development of Potent and Selective Phosphinic Peptide Inhibitors of Angiotensin-Converting Enzyme 2. J. Med. Chem. Vol. 51 (No.7): 2216-2226 - 117.
Mucha, A.; Pawelczak, M.; Hurek, J. & Kafarski, P. (2004) Synthesis and Activity of Phosphinic Tripeptide Inhibitors of Cathepsin C. Bioorg. Med. Chem. Lett. Vol. 14 (No. 12) 3113 – 3116 - 118.
Mucha, A.; Lämmerhoffer, M.; Lindner, W.; Pawelczak, M. & Kafarski, P. (2008) Individual Stereoisomers of Phosphinic Dipeptide Inhibitor of Leucine Aminopeptidase. Bioorg. Med. Chem. Lett. Vol. 18 (No. 5): 1550-1554 - 119.
Mucha, A.; Drag, M.; Dalton, J. P. & Kafarski, P. (2010) Metallo-Aminopeptidase Inhibitors. Biochimie Vol. 92 (No. 11): 1509 - 1529. - 120.
Mucha, A.; Kafarski, P. & Berlicki, L. (2011) Remarkable Potential of the -Aminophosphonate/Phosphinate Structural Motif in Medicinal Chemistry. J. Med. Chem. Vol. 54 (No. 17): 5955-5980 - 121.
Muo, L. & Schramm, V. L. (2008) Transition State Structure of E. coli tRNA-Specific Adenosine Deaminase. J. Am. Chem. Soc. Vol. 130 (No. 8): 2649-2655 - 122.
Murkin, A. S.; Birck, M. R.; Rinaldo-Matthis, A.; Shi, W.; Taylor, E. A.; Almo, S. C. & Schramm, V. L. (2007) Neighboring Group Participation in the Transition State of Human Purine Nucleoside Phosphorylase. Biochemistry Vol. 26 (No. 17): 5038-5049 - 123.
Mutahi, M.; Nittoli, T.; Guo, L.; Sieburth, S. McN. (2002) Silicon-based Metalloprotease Inhibitors: Synthesis and Evaluation of Silanol and Silanediol Peptide Analogues as Inhibitors of Angiotensin-converting Enzyme. J. Am. Chem. Soc. Vol. 124 (No. 25): 7363-7365 - 124.
Nelson, M. I. & Holmes, E. C. (2007) The Evolution of Epidemic Influenza, Nat. Rev, Genet. Vol. 8 (March 2007): 196-205 - 125.
Neuhaus, F. C. (2010) Role of Arg301 in Substrate Orientation and Catalysis in Subsite 2 of D-Alanine:D-alanine (D-Lactate) Ligase from Leuconostoc mesenteroides: A Molecular Docking Study. J . Mol. Graphics Model . Vol. 28 (No. 8): 728–734 - 126.
Nukaga, M.; Kumar, S.; Nukaga, K.; Pratt, R. F. & Knox, J. R. (2004) Hydrolysis of Third-generation Cephalosporins by Class C -Lactamases. J. Biol. Chem. Vol. 10 (No. 5): 9344-9352 - 127.
Osterman, N.; Eder, J.; Eidhoff, U.; Zink, F.; Hassiepen, U.; Worpenberg, S.; Mainbaum, J. Simic, O.; Hommel, U. & Gerhartz, B. (2006) Crystal Structure of Human BACE2 in Complex with a Hydroxyethylamine Transition-state Inhibitor. J. Mol. Biol. Vol. 355 (No.)2: 249-261 - 128.
Overall, C. M. & Kleifield O. (2006) Validating Matrix Metalloproteinases as Drug Targets and Anti-targets for Cancer Therapy Nat. Rev. Cancer Vol. 6 (No. 3): 227-239 - 129.
Palese, P.; Schulman, J. N.; Bodo, G. &Meindl, P. (1974). Inhibition of Influenza and Parainfluenza Virus Replication in Tissue culture by 2-Deoxy-2,3-dehydro-N-trifluoroacetylneuraminic Acid (FANA). Virology Vol. 59 (No. 2) 490–498. - 130.
Parks, J. M., Imhof, P. & Smith, J. C. (2010) Understanding Enzyme Catalysis Using Computer Simulation. Encyclopedia of Catalysis 2nd Ed. John Wiley & Sons 2010 - 131.
Pauling, L. (1949) Achievement and Hope for the Future. Am. Sci. Vol. 36: 50-58 - 132.
Pierdominici-Sottile, G.; Horenstein, N. A. & Roitberg A. E. (2011) Free Energy Study of the Catalytic Mechanism of T rypanosoma cruzi trans -Sialidase. From the Michaelis Complex to the Covalent Intermediate.Biochemistry Vol. 22 (No. 46): 10150-10158 - 133.
Pirard, B. (2007) Insight Into the Structural Determinants for Selective Inhibition of Matrix Metalloproteinases. Drug Discovery Today Vol. 12 (No.15/16): 640-646 - 134.
Pokorná, J.; Machala, L.; Řezáčova, P. & Konvalinka, J. (2009) Current and Novel Inhibitors of HIV Protease. Viruses Vol. 1 (No. 3): 1209-1239 - 135.
Polgár, L. (2005) The catalytic triad of serine peptidases. Cell. Mol. Life Sci. Vol. 62 (No. 19-20): 2161-2172 - 136.
Poreba, M.; Gajda, A.; Picha, J.; Jiráček, J.; Marschner, A.; Klein, C. D., Salvesen, G. S. & Drag, M. (2011) S1 Pocket Fingerprints of Human and Bacterial Methionine Aminopeptidases Determined Using Fluorogenic Libraries of Substrates and Phosphorus Based Inhibitors. Biochimie Vol. 94 (No. 3): 704-710 - 137.
Poreba M.; McGowan, S.; Skinner-Adams, T. S.; Trenholme, K. S.; Gardiner, D. L.; Whisstock, J. C.; To, J.; Salvesen, G. S.; Dalton, J. P. & Drag, M. (2012) Fingerprinting the Substrate Specificity of M1 and M17 Aminopeptidases of Human Malaria, Plasmodium falciparum. PLOS One Vol. 7 (No. 2): e31938 - 138.
Powell, J. R.; DeForrest, J. M.; Cushman, D. W.; Rubin, B. & Petrillo, E. W. (1984) Antihypertensive Effects of a New ACE Inhibitor, SQ. 28555. Fed. Proc. Vol. 43 (No. 3): 733 - 139.
Radzicka, A., and Wolfenden, R. (1995) Transition State and Multisubstrate Analog Inhibitors, Methods Enzymol. Vol. 249: 284-312 - 140.
Reiter, L. A.; Martinelli, G. J.; Reeves, L. A. & Mitchell, P. G. (2000) Difluoroketones as Inhibitors of Matrix Metalloprotease-13. Bioorg. Med. Chem. Lett. Vol. 10 (No.14): 1581-1584 - 141.
Reiter, L. A.; Mitchell, P. G.; Martinelli, G. J.; Lopresti-Morrow, L. L.; Yocum, S. A. & Escra, J. D. (2003) Phosphinic Acid-Based MMP-13 Inhibitors That Spare MMP-1 and MMP-3. Bioorg. Med. Chem. Lett. Vol. 13 (No. 14): 2331-2336 - 142.
Rejman, D.; Panova, N.; Klener, P.; Maswabi, B.; Pohl, R. & Rosenberg, I. (2012) N-Phosphonocarbonylpyrrolidine Derivatives of Guanine: A NewClass of Bi-Substrate Inhibitors of Human Purine Nucleoside Phosphorylase. J. Med. Chem. Vol. 55 (No. 4):1612-1621 - 143.
Rempel, B. R. & Withers, S. G. (2008) Covalent Inhibitors of Glycosidases and Their Applications in Biochemistry and Biology. Glycobiology Vol. 18 (No 8): 570-586 - 144.
Robertson, J. G. (2005) Mechanistic Basis of Enzyme-Targeted Drugs. Biochemistry Vol. 44 (No. 15): 5561-5571 - 145.
Rodnina, M. V.; Beringer, L. & Wintermeyer, W. (2006) How Ribosomes Make Peptide Bonds. Trends Biochem. Sci. Vol 31 (No.1): 20-26 - 146.
Sabina, R. L.; Paul, A.-L.; Ferl, R. J.; Laber, B. & Lindell, S. D. (2007) Adenine Nucleotide Pool Perturbation Is a Metabolic Trigger for AMP Deaminase Inhibitor-Based Herbicide Toxicity. Plant Physiol. Vol. 143 (No. 4): 1752-1760 - 147.
Saen-oon, S.; Quaytman-Machleder, S.; Schramm, V. L. & Schwartz, S. D. (2008) Atomic Detail of Chemical Transformation at the Transition State of an Enzymatic Reaction. PNAS Vol. 105 (No. 43): 16543-16545 - 148.
Sang, Q.-X. A.; Jin, Y.; Newcomer, R. G.; Monroe, S. C.; Fang, X.; Hurst, D. R.; Lee, S.; Cao, Q. & Schwartz, M. A. (2006) Matrix Metalloproteinase Inhibitors as Prospective Agents for the Prevention and Treatment of Cardiovascular and Neoplastic Diseases. Curr. Top. Med. Chem. Vol. 6 (No. 4): 289-316 - 149.
Schramm, V. L. (2002) Development of Transition State Analogues of Purine Nucleoside Phosphorylase as Anti-T-cell Agents. Biochim. Biophys. Acta Vol. 1587 (No. 2-3): 107-117 - 150.
Schramm, V. L. (2005) Enzymatic Transition States and Transition State Analogues. Curr. Opin. Struct. Biol. Vol. 15 (No. 7): 604-613 - 151.
Schramm, V. L. (2007) Enzymatic Transition State Theory and Transition State Analogue Design. J. Biol. Chem. Vol. 282 (No. 39): 28297-28300 - 152.
Schramm, V. L. (2011) Enzymatic Transition States, Transition-State Analogs, Dynamics, Thermodynamics, and Lifetimes. Annu. Rev. Biochem. Vol. 80: 703-732 - 153.
Schwartz, P. A.; Vetticatt, J. & Schramm V. L. (2010) Transition State Analysis of Thymidine Hydrolysis by Human Thymidine Phosphorylase. J. Am. Chem. Soc. Vol. 132 (No. 38): 13425-13433 - 154.
Senn, H. M. & Thiel, W. (2007) QM/MM Studies of Enzymes. Curr. Opin. Chem. Biol. Vol. 11 (No. 2): 182-187 - 155.
Shi, W.; Wu, C. M.; Tyler, P.C.; Furmeaux, R. H.; Cahill, S. M.; Girvin, M. E.; Grubmeyer, C.; Schramm, V. L & Almo, S.C. (1999) The 2.0 Å Structure of Malarial Purine Phosphoribosyltransferase in Complex with a Transition-State Analogue Inhibitor. Biochemistry Vol. 38 (No. 31): 9872-9880 - 156.
Shie, J. J.; Fang, J. M.; Wang, S. Y.; Tsai, K. C.; Chemg, Y.-S. E.; Yang, A. S.; Hsiao, S. C.; Su, C. Y. & Wong C. H. (2007) Synthesis of Tamiflu and its Phosphonate Congeners Possessing Potent Anti-Influenza Activity. J. Am. Chem. Soc. Vol. 129 (No. 39): 11892-11893 - 157.
Shin, H.; Cama, E. & Christianson, D. W. (2004) Design of Amino Acid Aldehydes as Transition-State Analogue Inhibitors of Arginase. J. Am. Chem. Soc. Vol. 126 (No. 33): 10278-10284 - 158.
Shishova, E. Y.; Di Costanzo, L.; Emig, S. A.; Ash, D. E. & Christianson, D. W. (2009) Probing the Specificity Determinants of Amino Acid Recognition by Arginase. Biochemistry Vol. 48 (No. 1): 121-131 - 159.
Sieburth, S. McN. & Chen, C.-A. (2006) Silanediol Protease Inhibitors: From Conception to Validation. Eur. J. Org. Chem. Vol. 2006 (No. 2): 311-322 - 160.
Skinner-Adams, T.; McCarthy, J. S.; Gardiner, D. L.; Hilton, P. M.& Andrews, K. T. (2004) Antiretrovirals as Antimalarial Agents. J. Infect. Dis . Vol. 190 (No. 11); 1998-2000 - 161.
Skinner-Adams, T. S.; Lowther, J.; Teuscher, F.; Stack, C. M.; Grembecka, J.; Mucha, A.; Kafarski, P.; Trenholme, K. R.; Dalton, J. P.; & Gardiner, D. L.(2007) Identification of Phosphinate Dipeptide Analog Inhibitors Directed Against the Plasmodium falciparum M17 Leucine Aminopeptidase as Lead Antimalarial Compounds.J. Med. Chem. Vol. 50 (No. 24): 6024 - 6031. - 162.
Skinner-Adams, T. S.; Stack, C. M.; Trenholme, K. R.; Brown, C. L.; Grembecka, J.; Lowther, J.; Mucha, A.; Drag, M.; Kafarski, P.; McGowan, S.; Whisstock, J. C.; Gardiner, D. L. & Dalton, J. P. (2010) Plasmodium falciparum Neutral Aminopeptidases: New Targets for Anti-malarials.Trends Biochem. Sci. Vol. 35 (No. 1): 53 – 61 - 163.
Silva, R. G.; Hirschi, J. S.; Ghanem, M.; Murkin, A. S.; & Schramm, V. L. (2011) Arsenate and Phosphate as Nucleophiles at the Transition States of Human Purine Nucleoside Phosphorylase. Biochemistry, Vol. 50 (No. ): 2701-2709 - 164.
Stack, C. M.; Lowther, J.; Cunningham, E.; Donnelly, S.; Gardiner, D. L.; Trenholme, K. R.; Skinner-Adams, T. S.; Teuscher, F.; Grembecka, J.; Mucha, A.; Kafarski, P.; Lua, L.; Bell, A. & Dalton, J. P. (2007) Characterization of the Plasmodium falciparum M17 Leucyl Aminopeptidase. A Protease Involved in Amino Acid Regulation with Potential for Antimalarial Drug Development.J. Biol. Chem. Vol. 282 (No. 3): 2069 – 2080 - 165.
Stanley, M.; Cattle, N.; McCauley, J.; Martin, S. R.; Rashid, A.; Field, R. A.; Carbain, B. & Streicher, H. (2012) ‘TamiGold’: Phospha-oseltamivir-Stabilised Gold Nanoparticles as the Basis for Influenza Therapeutics and Diagnostics Targeting the Neuraminidase (Instead of the Hemagglutinin). MedChemComm doi: 10.1039/c2md20034a - 166.
Streicher, H. & Busse, H. (2006) Building a Successful Structural Motif into Sialylmimetics - Cyclohexenephosphonate Monoesters as Pseudo-sialosides with Promising Inhibitory properties. Bioorg. Med. Chem. Vol. 14 (No. 4): 1047-1057 - 167.
Sumida, T.; Stubbs, K. A.; Ito, M. & Yokohama, S. (2012) Gaining Insight into the Inhibition of Glycoside Hydrolase Family 20 exo--N-Acetylhexosaminidases Using a Structural Approach. Org. Biomol. Chem. Vol. 10 (No. 13): 2607-2612 - 168.
Teuscher, F.; Lowther, J.; Skinner-Adams, T.S.; Spielmann, T.; Dixon, M.W.A.; Stack, C.M.; Donnelly, S.; Mucha, A.; Kafarski, P.; Vassiliou, S.; Gardiner, D.L.; Dalton, J.P.; Trenholme, K. (2007) The M18 Aspartyl Aminopeptidase of the Human Malaria Parasite Plasmodium falciparum .J. Biol. Chem. Vol. 282 (No. 42): 30817 – 30826 - 169.
Thivierge, K.; Mathew, R. T.; Nsangou, D. N. N.; Da Silva, F.; Cotton, S. Skinner-Adams, T. S.; Trenholme, K. R.; Brown, C. L.; Stack, C. M.; Gardiner D. M. & Dalton, J. P. (2012) Anti-malaria Drug Development Targeting the M1 Alanyl and M17 Leucyl Aminopeptidases. ARKIVOC 2012 (No. 4): 330-346 - 170.
Thomson, J. M.; Prati, F.; Bethel, C. R. & Bonomo, R. A. (2007) Use of Novel Boronic Acid Transition State Inhibitors To Probe SubstrateAffinity in SHV-Type Extended-Spectrum -Lactamase. Antimicrob. Agents Chemother. Vol. 51 (No. 4): 1577-1579 - 171.
Trippier P. C. & McGuigan, C. (2010) Boronic Acids in Medicinal Chemistry: Anticancer, Antibacterial and Antiviral Applications. Med. Chem. Commun. Vol. 1 (No. 3): 183-198 - 172.
Tuan, H. F.; Erskin, P.; Langan, P. Cooper, J. & Coates, L. (2007) Preliminary neutron and ultrahigh-resolution X-ray diffraction studies of the aspartic proteinase endothiapepsin cocrystallized with a gem-diol inhibitor. Acta Crystallogr. Vol. 63 (No. 12): 1080-1083 - 173.
Turcotte, S.; Bouayad-Gervais, H. & Lubell, W. (2012) N-Aminosulfamide PeptideMimic Synthesis by Alkylation of Aza-sulfurylglycinyl Peptides. Org. Lett. Vol. 14 (No. 5): 1318-1321 - 174.
Tyler, P. C.; Taylor, E. A.; Fröhlich, F. R. G. & Schramm, V. L. (2007) Synthesis of 5‘-Methylthio Coformycins: Specific Inhibitors for Malarial Adenosine Deaminase. J. Am. Chem. Soc. Vol. 129 (No. 21): 6872-6879 - 175.
Udommaneethanakit, T. Rungrotmongkol, T.; Bren, U.; Frecer, V. & Miertus, S. (2009) Dynamic Behavior of Avian Influenza A Virus Neuraminidase Subtype H5N1 in Complex with Oseltamivir, Zanamivir, Peramivir, and Their Phosphonate Analogues. J. Chem. Inf.Model. Vol. 49 (No.10): 2323-2332 - 176.
Umezawa, H.; Aoyagi, T.; Suda, H.; Hamada, M. & Takeuchi, T. (1976) Bestatin, an Inhibitor of Aminopeptidase B, Produced by Actinomycetes. Journal of Antibiotics (Tokyo) Vol. 29 (No. 1): 97-99 - 177.
Vasella, A.; Davies, G. J. & Böhm, M (2002) Glycosidase Mechanisms. Curr. Opin. Chem. Biol. Vol. 5 (No. 6): 619-629 - 178.
Vassiliou, S.; Xeilari, M.; Yiotakis, A.; Grembecka, J.; Pawelczak, M.; Kafarski, P. & Mucha, A. (2007) A Synthetic Method for Diversification of the P1' Substituent in Phosphinic Dipeptides as a Tool for Exploration of the Specificity of the S1' Binding Pockets of Leucine Aminopeptidases. Bioorg. Med. Chem. Vol. 15 (No. 9): 3187 – 3200 - 179.
Vassiliou, S.; Grabowiecka, A.; Kosikowska, P.; Yiotakis, A.; Kafarski, P. & Belicki, Ł. (2008) Design, Synthesis, and Evaluation of Novel Organophosphorus Inhibitors of Bacterial Ureases. J. Med. Chem. Vol. 51 (No. 18): 5736-5744 - 180.
Vassiliou, S.; Grabowiecka, A.; Kosikowska, P. & Berlicki, L. (2012) Three Component Kabachnik-Fields Condensation Leading to Substituted Aminomethane-P-hydroxymethylphosphonic Acids as a Tool for Screening of Bacterial Urease Inhibitors. ARKIVOC Vol. 2012 (No. 4): 33-43 - 181.
Weinger, J. S.; Kitchen, D.; Scaringe, S. A.; Strobel, S. A. & Muth, G. W. (2004) Solid Phase Synthesis and Binding Affnity of Peptidyl Transferase Transition State Mimics Containing 2'-OH at P-site Position A76. Nucl. Acids Res. Vol. 32 (No. 4):1502-1511 - 182.
Venkatraman, S.; Wu, W.; Prongay, A.; Girijavallabhan, V. & Njoroge, F. G. (2009) Potent Inhibitors of HCV-NS3 Protease Derived from Boronic Acids. Bioorg. Med. Chem. Lett. Vol. 19 (No. 1): 180-183 - 183.
Verma, R. P. & Hansch, C. (2007) Matrix Metalloproteinases (MMPs): Chemical–Biological Functions and (Q)SARs. Bioorg. Med. Chem. Vol. 15 (No. 6): 2223-2268 - 184.
Wei, D.-Q.; Du, Q.-S.; Sun, H. & Chou, K. H. (2006) Insights from Modeling the 3D Structure of H5N1 Influenza Virus Neuraminidase and its Binding Interactions with Ligands. Biochem. Biophys. Res. Commun. Vol. 344 (No. 3): 1048-1055 - 185.
Wheatley, J. L. & Holyoak, T. (2007) Differential P1 Arginine and Lysine Recognition in the Prototypical Proprotein Convertase Kex2. Proc. Natl. Acad. Sci. U.S.A. Vol. 104 (No. 16): 6626-6631 - 186.
Williams, I. H. (2010) Catalysis: Transition-state Molecular Recognition? Beilstein J. Org. Chem. Vol. 6: 1026-1034 - 187.
Wolfe, M. S. (2012) -Secretase Inhibitors and Modulators for Alzheimer's Disease. J. Neurochem. Vol. 120 (Suppl. 1): 89-98 - 188.
Wolfenden, R. (1972) Analogue Approaches to the Structure of the Transition State in Enzyme Reactions. Acc. Chem. Res. Vol. 5: 10-18 - 189.
Wolfenden, R. (1976) Transition State Analog Inhibitors and Enzyme Catalysis, Annu. Rev. Biophys. Bioeng . Vol. 5: 271-306 - 190.
Wolfenden, R. (1999) Conformational Aspects of Inhibitor Design: Enzyme-Substrate Interactions in the Transition State. Bioorg. Med. Chem. Lett. Vol. 7 (No. 5): 647-652 - 191.
Wolfenden, R. (2003) Thermodynamic and Extrathermodynamic Requirements of Enzyme Catalysis. Biophys. Chem. Vol. 105 (No. 2-3): 559-572 - 192.
Wood, J. M.; Maibaum, J.; Rahuel, J.; Grütter, M. G.; Cohen, N. C.; Rasetti, V.; Rüger, H.; Göschke, R.; Stutz, S.; Fuhrer, W.; Schilling, W.; Rigollier, P.; Yamaguchi, Y.; Cumin, F.; Baum, H.-P.; Schnell, C. R.; Herold, P.; Mah, R.; Jensen, C.; O’Brien, E.; Stanton, A. & Bedigian, M. P. (2003) Structure-based Design of Aliskiren, a Novel Orally Effective Renin Inhibitor. Biochem. Biophys. Res. Commun. Vol. 308 (No.4): 698-705 - 193.
Wu., X.; Öhrngren, P.; Ekegren, J. K.; Unge, J.; Unge, T.; Wallberg, H.; Samuelssom, B.; Hallberg, A. & Larhed, M. (2008) Two-Carbon-Elongated HIV-1 Protease Inhibitors with a Tertiary-Alcohol-Containing Transition-State Mimic. J. Med. Chem. Vol. 51 (No.): 1053-1057 - 194.
Wu, D.; Zhang, L.; Kong, Y.; Du, J.; Chen, S.; Chen, J.; Ding, J.; Jiang, H. & Shen, X. (2008a) Enzymatic Characterization and Crystal Structure Analysis of the D-Alanine-D-alanine Ligase from Helicobacter pylori. Proteins Vol. 72, (No. 4): 1148–1160 - 195.
Xu, W.; Cheng, G.; Liew, O. W.; Zuo, Z.; Jiang, H. & Zhu, W. (2009) Novel Non-peptide -Secretase Inhibitors Derived from Structure-based Virtual Screening and Bioassay. Bioorg. Med. Chem. Lett. Vol. 19 (No. 12): 3188-3192 - 196.
Yiotakis, A.; Georgiadis, D.; Matziari, M. & Dive, V. (2004) Phosphinic Peptides: Synthetic Approaches and Biochemical Evaluation as Zn-Metalloprotease Inhibitors. Curr. Org. Chem. Vol. 8 (No. 12): 1135-1158 - 197.
Zambelli, B.; Musialini, F., Benini, S. & Ciurli, S. (2011) Chemistry of Ni2+ in Urease: Sensing, Trafficking, and Catalysis. Acc. Chem. Res. Vol. 44 (No. 7): 520-530 - 198.
Zhang, X.; Schmitt, A. C.; Jiang, W.; Wasserman, Z. & Decicco, C. P. (2003) Design and Synthesis of Potent, Non-peptide Inhibitors of HCV NS3 Protease. Bioorg. Med. Chem. Lett. Vol. 13 (No.6): 1157-1160 - 199.
Zhang, X. & Xu, W. (2008) Aminopeptidase N (APN/CD13) as a Target for Anti-cancer Agent Design. Curr. Med. Chem. Vol. 15 (No.27): 2850-2865 - 200.
Zucker, S. & Cao, J. (2009) Selective Matrix Metalloproteinase (MMP) Inhibitors in Cancer Therapy. Cancer Bio. Ther. Vol. 8 (No. 24): 2371-2323