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Gaucher disease (GD) is an inherited metabolic disorder caused by the deficiency of enzyme acid β-Glucosidase resulting in the deposition of harmful quantities of lipids/fats. To date, enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) are the only modes of treatment approved by the FDA for Gaucher disease. In this study, we evaluated the ability of microbial bioactive compounds as a drug candidate. The treatment based on molecular docking against selected protein targets plays a crucial role in the future treatment of this disease. Microbial compounds contain bioactive compounds in the form of alkaloids and others of natural origin. Through molecular docking the deep binding affinity of 10 selected compounds present in algae, bacteria, and fungi against the enzyme acid β-Glucosidase of GD using Maestro Schrodinger software, in addition, the ADMET properties are also predicted. Out of these compounds, Lipoxazolidinone C, Cinnamic acid, and Marinopyrrole A, have a sturdy interaction with the Gaucher disease target enzyme, and it can be considered as an effective drug target for Gaucher disease. Our findings reveal a novel discovery towards biology mainly pointing to microbes as a drug formulation. Further, these compounds could be analyzed for their stability through molecular dynamics techniques.
Department of Botany, PSG College of Arts and Science, Coimbatore, TN, India
Amritha Pozhaiparambil Sasikumar*
Department of Zoology, PSGR Krishnammal College for Women, Coimbatore, TN, India
*Address all correspondence to: amritha3097@gmail.com
1. Introduction
Ethnomedicine is the study of traditional medicine based on the bioactive compounds of plants and animals, the mother of all other systems of medicines- Ayurveda, Siddha, Unani, Naturopathy, and even modern medicine. These ethnomedicine have played a major role throughout the world in treating and preventing diseases. The various sources of natural medicinal products could be terrestrial plants, terrestrial microbes, marine microbes, and even vertebrates and invertebrates [1].
During the ‘golden era’ of antibiotic discovery, the generation time of pathogens varies from minutes to weeks, leading to the inevitability of resistance selection. This reinforced the need for new chemical entities. The two novel antibiotics that are approved by FDA for human use are linezolid and daptomycin. There is a need for the discovery of an alternative drug using natural medicinal products.
Microorganisms are ubiquitous interact with all other organisms and inhabit every environment on Earth. These are the leading producers of the useful natural products, indicating their excellency in drug formulation. Various portions of microbial genomes are devoted to production of secondary metabolites. Recently, scientists have begun to realize and discover their role in the medical community. These are an ample source of structurally diverse bioactive substances which have led to the discovery of drugs mainly penicillin, cephalosporins, polyketides, and tetracyclines [2]. A single microbe can produce several the secondary metabolites. They include antibiotics, anticancer agents, immunosuppressants, anthelmintics, and many more. With the development of Computer technology, in silico approaches have been widely used to elucidate the pharmacological use of plants and microbes in drug discovery [3]. Therefore the ‘new era’ of drug discovery is believed to prevent and control the consequence of disease and illness in a more rational way [4]. Generally, microorganisms are differentiated on the basis of their cellular organization as shown in Figure 1.
Figure 1.
Microbial classification based on cellular organization.
According to National Organization for Rare Diseases (NORD), Gaucher Disease (GD) is an orphan disease, an inherited metabolic disorder in which deficiency of the enzyme β- glucosidase results in the accumulation of harmful quantities of lipids/fats. Especially the glycolipid glucocerebroside, throughout the body especially within the bone marrow, spleen, and liver. Researchers have identified three distinct forms of GD: Type 1 - Non-neuronopathic GD, Type 2 - Acute neuronopathic GD, Type 3- Chronic neuronopathic GD [5]. The gene mutations lead to the replacement of amino acids in the enzyme β- glucosidase which reduces the protein stability and the catalytic activity. Personalized treatment is required depending on the type of GD.
The drug therapy options approved by FDA include (ERT) Enzyme Replacement Therapy and (SRT) Substrate Reduction Therapy [6, 7]. The cost of ERT and SRT are very high as for most orphan drugs. These kinds of treatment measures are not available for rural people as they are unaware due to the lack of facilities in hospitals. The ultimate aim of the study is the application of virtual screening and network pharmacology which enriches the active compounds among the candidates, thereby indicating the action mechanism of beneficial microbes, reducing the cost, and increasing the efficiency of the whole procedure, seeking an alternative solution for GD.
In our study, we construct the network of relationships among the medicinal microbes, their natural compounds, and the biological targets of the diseases. We hereby performed a deep virtual screening process through the molecular docking studies to test the binding efficiency of selected bioactive compounds from the microbes as a drug candidate. This is first in-silico work using the microbes as the core elements for the therapeutic studies against the GD, which brings out the novelty of the work carried out, attempting to find an alternative solution for GD.
The structure-based drug designing was performed, which serves as a powerful tool in identifying new lead compounds in the process of drug discovery [8]. The sources of the chemicals from the microbes are purely based on the literature work done intensively during the whole work.
2.1 Databases
The 3D protein structure was retrieved from Protein Data Bank. All the corresponding ligand molecules were retrieved after intensive literature review from various online sources and the 2D structure of these bioactive compounds were retrieved from PubChem (https://pubchem.ncbi.nlm.nih.gov/).
2.2 Protein preparation
The proteins were assembled by removing the native auto inducer all water molecules. Hydrogen was re-added using the protein residue template in Maestro v10.2. This is a vital stage in the preparation of protein as any modification can be re-addressed like missing side chains, and updating the missing residues. To enhance the structure the water molecules were removed, increasing the entropy of the target molecule.
2.3 Ligand preparation
Initially the ligands were converted into 3D structure using the Ligprep tool in maestro Schrödinger v10.2. The ligand was geometrically optimized.
2.4 ADMET activity
An account of druggability is very essential while performing a docking study, the ligands were checked for Absorption, distribution, metabolism, excretion, and toxicity (ADMET) test. It is a preliminary step in drug preparation. The knowledge on drugs for Gaucher disease is very scanty, and it is very reasonable to make out more and reduce the cost of treatment as a lot of developing countries can rely on it. 12 compounds successfully scored well in all the ADMET parameters analyzed using Qikprop version 4.4. in the Schrodinger suite [9]. Some important parameters like CNS, Blood-barrier coefficient, human blood absorption, Lipinski’s rule of three and five were analyzed. The bioactive phyto-compounds which displayed pragmatic result were chosen for the ADME and preferable docking poses has been tabbed for the rationale of docking [10].
2.5 Molecular docking
Molecular docking outlays the ligand’s preferred orientation with the target molecule while interacting with each other in forming a highly stable complex. For this purpose, we have employed Maestro v10.2 to conduct the extra precision (XP) docking for speculating the binding affinity, analyzing the efficacy of the ligand, and inhibitory constant of ligand against the target. In this study, the entire ligand was docked with the target molecule flexibly using the Glide Xtra precision (XP) tool. As a result of successful docking, we have obtained better docking scores, poses with accurate hydrophobic contacts between target residues to ligand [11].
2.6 PyMOL
PyMOL is an open-source molecular visualization tool commercialized by Schrödinger, which can produce high-quality 3D images of small molecules, biological macromolecules like proteins. It is one of the most trusted tools for visualization in structural biology and it operates on Python language.
2.7 LigPlot
A computer program able to generate 2D schematic representation of protein-ligand interaction from the standard PDB input file. The interactions shown are basically of hydrogen bonds and hydrophobic contacts. In this hydrogen bonds are indicated by dashed lines between the atoms involved whereas hydrophobic interactions are represented by an arc with spokes facing towards the ligand atoms they come in contact with. The interacted atoms are represented by the spokes facing them back [12].
The ADMET (Adsorption, Distribution, Metabolism, Excretion, and Toxicity) analysis was performed for evaluating the drug-likeness of 50 compounds from microorganisms. The prediction was performed using the Quikprop version 4.4 in the Schrodinger suite [8]. Drug likeness properties of the selected compounds were determined by Lipinski’s rule of five, Jorgensen’s rule of three, molecular weight, CNS activity, dipole movement, Volume, Total solvent accessible surface area (SASA), Brain/blood partition coefficient, metabolic reactions, Human oral absorption and Percent Human Oral Absorption. It is believed that ADME shows the toxicity of small molecules [13]. The drug-like property’s prediction was then evaluated and the results were portrayed in Table 1.
Name of compound (PDB Id)
Molecular weight
Volume
Dipole movement
SASA
Donor HB
Accpt HB
#metab
QPlog BB
CNS
Human oral absorption
Percent human oral absorption
Rule of five
Rule of three
Lipoxazolidinone C (23642823)
307.432
1195.068
4.198
702.848
0
4.5
3
−1.204
−2
3
100
0
0
Cinnamic acid (444539)
148.161
568.531
6.693
369.072
1
2
0
−0.565
−1
3
79.474
0
0
Marinopyrrole A (24797083)
510.16
1230.393
5.425
639.808
1
3.5
2
−0.456
0
1
83.287
2
1
Chlorohydroaspyrone B (25016145)
220.652
699.441
3.611
421.719
1
5.4
2
−0.583
0
3
81.892
0
0
Chlorohydroaspyrone B (24900165)
341.409
1114.774
3.441
627.858
3
6.7
6
−1.239
−2
3
79.198
0
0
Racemosin A (155148)
288.299
882.289
8.137
495.888
0
4.75
2
−0.157
0
3
100
0
0
Apralactone A (102411411)
332.352
968.272
6.07
518.358
2
6.25
4
−0.852
−1
3
80.909
0
0
LBM-415 (9690139)
396.418
1245.941
4.227
697.146
2
10.7
3
−1.868
−2
2
58.058
0
0
Spirotryprostatin B (9928968)
363.415
1120.217
4.923
610.282
1
8.5
4
−0.829
−1
3
85.127
0
0
Dehydrocurvularin (6438143)
290.315
903.643
6.955
510.217
1
4.5
4
−1.03
−2
3
80.753
0
0
Table 1.
Analysis of ADMET properties for the microbial compounds.
ADME is an essential tool for analyzing the proposed molecule’s oral bioavailability as possible drugs. Statistics estimate that almost half of the candidate drugs do not undergo clinical trials because they fail to meet the suitable levels of efficacy, toxic effect on the body, making it unsafe for human use [14]. According to the literature study, 50 compounds were selected for ADME Analysis, from which the prediction results were shown by the 10 compounds from different microorganisms, especially bacteria, fungi, and algae (Figure 2).
Figure 2.
Bioavailability of microbial compounds before and after ADMET analysis.
3.2 Molecular docking
Computational docking was implemented to predict binding of the 10 compounds (Figure 3) which represents alkaloids, antibacterial, antimicrobials from microorganisms mainly bacteria, fungi, and algae with acid β-glycosidase as the target protein.
Figure 3.
2D chemical structures of the selected microbial bioactive compounds.
Glide Score is an empirical scoring function that approximates the ligand binding free energy, including force field (electrostatic, van der Waals) contributions It highlights docking accuracy, database enrichment, and binding affinity prediction. Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand.
Out of 10 microbial bioactive compounds, Lipoxazolidinone C, Marinopyrrole A, LBM-415, were the promising bacterial compounds, Cinnamic acid, Chlorohydroaspyrone B, 14-hydroxyterezine D, Apralactone A, Spirotryprostatin B, and Dehydrocurvularin belongs to the fungal compounds, and Racemosin A is the only compound belonging to algae. The binding scores of each compound with the target protein acid β-glycosidase are depicted in Table 2.
Name of the compound (PBD ID)
Microbe species
G. Score
Residues interacted
Bond length (Å)
Total number of bonds
Lipoxazolidinone C (23642823)
Marinispora sp.
−10.56
GLU-482 (H-O)
2.1
1
Cinnamic acid (444539)
Cladosporium sp.
−10.33
ASN-377 (O-H)
2
1
Marinopyrrole A (24797083)
Strepttomyces saccurensis
−9.6
SER-447 (O-H)
2.6
4
GLU-446 (H-O)
1.9
ASN-377 (H-O)
2.3
ASN-377 (H-O)
2.3
Chlorohydroaspyrone B (25016145)
Exophiala sp.
−9.17
SER-447 (O-H)
2.2
3
ASN-262 (O-H)
2.1
ASN-377 (H-O)
1.7
14-hydroxyterezine D (24900165)
Aspergillus sydowi
−8.82
ARG-444 (O-H)
2
1
Racemosin A (155148)
Caulerpa racemosa
−8.44
ASN-262 (O-H)
2.8
2
(O-H)
1.9
Apralactone A (102411411)
Curvularia sp.
−8.31
ASN-377 (H-O)
1.8
3
GLY-379 (O-H)
2.1
GLU-446 (O-H)
2.5
LBM-415 (9690139)
Streptomyces sp.
−7.77
GLU-446 (O-H)
2
2
GLY-379 (O-H)
2.1
Spirotryprostatin B (9928968)
Aspergillus sydowi
−7.4
GLU-446 (H-O)
2.1
1
Dehydrocurvularin (6438143)
Curvularia sp.
−6.06
ARG-252 (O-H)
1.9
3
ASN-262 (O-H)
1.8
GLU-211 (H-O)
1.9
Table 2.
Docking scores of β- glucosidase with microbial compounds.
Among the 10 ligands, the compound Lipoxazolidinone C from Marinispora sp (Bacteria) had the least Glide score of −10.56 Kcal/mol (Table 2). The binding mode for Lipoxazolidinone C to acid β-glycosidase was attributed to H-bond interaction with GLU 482 with a bond length of 2.1 Å, while amino acid residue ASN 377 was positioned at a distance of H-bond with a bond length of 2.0 Å with Cinnamic acid from Cladosporium sp. of fungi with a glide score of −10.33 Kcal/mol. The third docking scores were received by the ligand Marinopyrrole A from Streptomyces saccurensis (Bacteria) with a Glide score of −9.6 Kcal/mol. Marinopyrrol A interacts with SER 447, GLU 446, ASN 377 forming four H-bonds of length 2.6, 1.9, 2.3, 2.3 Å respectively. Followed by the Glide score of −9.17 Kcal/mol was Chlorohydroaspyrone B from the microbe Exophiala sp. (Fungi). The residues were SER 477, ASN 262, and ASN 377 forming three H-bonds with the bond lengths of 2.2, 2.1, and 1.7 Å respectively, while amino acid residues ARG 444 were positioned at a distance of 2.0 Å of H-bond with ligand 14-hydroxyterezine D from Aspergillus sydowi (Fungi) with a Glide score of −8.82 Kcal/mol (Figure 4).
Figure 4.
The docking complex of (a) Lipoxazolidinone C, (b) Cinnamic acid, (c) Marinopyrrole a, (d) Chlorohydroaspyrone B, and (e) 14-hydroxyterezine D with the X-ray structure of acid β-glucosidase. 3D interaction (left) and 2D schematic diagram using Ligplot (right).
In addition, Racemosin A from Caulerpa racemose (Algae) interacts with ASN 262 with two H-bonds, while amino acid residues ASN 377, GLY 379, and GLU 446 are positioned at a distance of H-bond with Apralactone A which is obtained from Curuvularia sp. (Fungi). LBM-415 from Streptomyces sp. (Bacteria) interacts with GLU 446 and GLY 379 with two H-bonds, while amino acid residues GLU 446 are positioned at a distance of H-bond with Spirotryprostatin B from Aspergillus sydowi (Fungi). Last but not the least, the microbial ligand Dehydrocurvularin from Curvularia sp. (Fungi) interacted with the target protein with residues ARG 252, ASN 262, and GLU 211 forming three H-bonds. Taken together we propose the above indicated microbial bioactive compounds as a candidate for drug for GD, thus limiting viral maturation.
Secondary metabolites of microbial origin have been proven to be an important source for new pharmaceuticals and drug lead candidates like antibacterial agents like penicillin, an antifungal drug like echinocandin B, cholesterol-lowering agent lovastatin, and more [15].
In line with our findings, the bioactive compound Lipoxazolidinone C has unusual 4-oxazolidinone heterocycle at its core, representing a wide spectrum of antibacterial and anti-microbial activity similar to those of the commercial antibiotic linezolid (Zyvox) [16]. Another study suggests that 4-oxazolidinones are valuable scaffolds of antimicrobial development [17]. Cinnamic acid and its phenolic analogs are natural substances. Isopropyl 4-hydroxycinnamate and butyl 4-hydroxycinnamate were found to have almost similar antifungal activity as commercial fungicide iprobenfos against Pythium sp. [18]. For decades, cinnamic acid and its derivatives have attained huge attention for their anticancer as well as antitumor potentials [19]. Similarly, cinnamic, coumaric, ferulic, and sinapic acids show inhibitory activity against several Gram-positive and Gram-negative bacteria [20] and have been found to be potential natural antifouling agents inhibiting larval settlement of Balanus neritina [21]. The marine natural product, marinopyrrole A has been shown to have potent antibiotic activity against Gram-positive pathogens [22]. According to the data of ChEBI, the biological roles of marinopyrrole A are marine, bacterial metabolite, as well as antimicrobial, antibacterial, and antineoplastic agents. Due to the antibiotic and cytotoxicity, marinopyrrole A and its derivatives are possible for SAR studies [23]. The cultural broth of marine fungal strain from genus Exophiala produced new aspyrone derivatives called Chloroaspyrones A and B. Both the compounds displayed moderate to weak antibacterial activity when tested against S. aureus [24]. 14-hydroxyterezine is a type of diketopiperazine alkaloids, isolated from ethyl acetate of Aspergillus sydowi, exhibits weak cytotoxicity against human alveolar basal carcinoma A-549 cells [25]. Racemosin A is a unique bisindole alkaloid possessing a structure derived from a green alga. Studies suggest that Racemosin A significantly attenuates the Aβ25-35 induced SH-SY5Y cell damage with an increase in cell viability in a neuro-protective assay [26] and shows anti-cancer activity exhibiting a strong inhibitor against human breast cancer cell lines [27]. Apralactone A has shown moderate concentration-dependent cytotoxicity in 36 cancer cell line panels, playing an important role in the development of anticancer drugs [28]. In vitro drug susceptibilities tests and in vivo characterization in an animal model showed that LBM-415 had a good antimicrobial activity that is equivalent to the marketed antibiotic agents [29]. LBM 415 is the first peptide deformylase (PDF) inhibitor class being developed for clinical trials for oral and parenteral treatment for the respiratory tract, and skin structure infections caused by susceptible gram-positive and gram-negative organisms [30]. In an experiment, scientists isolated a novel compound named Spirotryprostatin B which inhibited the cell cycle progression of tsFT210 cells at the G2/M phase, in addition, they show cytotoxic activity on the growth of human chronic myelogenous leukemia K562 cells and human promyelocytic leukemia HL-60 cells [31]. In a recent study, Dehydrocurvularin (DCV) was revealed to have a potent irreversible inhibitor of ATP-citrate lyase (ACLY) through classical chemoproteomic profiling indicating the anti-cancer mode of action of DCV [32]. Similarly, dehydrocurvularin was found to be a fungal metabolite during the screening of fungal metabolites inhibiting TGF-β dependent signaling [33].
The present molecular docking analysis of microbial compounds against Gaucher disease (GD) target protein acid beta-glucosidase has prominent favorable compounds of natural origin with good binding to the Gaucher disease target. Lipoxazolidinone C, Cinnamic acid, and Marinopyrrole A are the most prominent compounds on the Gaucher enzyme target sites. These bioactive compounds were also found to display good antibacterial, antimicrobial, antibiotic, and antifungal activity against various human pathogens. In summary and from the theoretical evidence based on previous in-vitro confirmatory studies, we recommend further in-vivo investigation assessment to analyze the predicted affinity of the selected bioactive compounds against the Gaucher Disease.
Amritha P S and Sreeram S have drafted the manuscript, and collected the articles. Sreeram. S has done the PyMOL visualizations and Amritha P.S. reviewed the manuscript.
This article does not contain any studies involving animals performed by any of the authors. This article does not contain any human participants involving performed by any of the authors.
Not applicable as no clinical trials were involved in this study.
Availability of data and material
All data generated or analyzed during this study are included in this published article.
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Written By
Sreeram Sudhir and Amritha Pozhaiparambil Sasikumar
Submitted: 01 July 2022Reviewed: 01 September 2022Published: 27 October 2022
Open access peer-reviewed chapter
