Exploring Toxins for Hunting SARS-CoV-2 Main Protease Inhibitors: Molecular Docking, Molecular Dynamics, Pharmacokinetic Properties, and Reactome Study
Abstract
:1. Introduction
2. Results and Discussion
2.1. Validation of In Silico Protocol
2.2. T3DB Database Virtual Screening
2.3. Molecular Dynamics (MD) Simulations
2.4. Post-MD Analyses
2.4.1. Binding Energy per Frame
2.4.2. Intermolecular Hydrogen Bonds
2.4.3. Center-of-Mass Distance
2.4.4. Root-Mean-Square Deviation
2.5. Drug-like Properties
2.6. In Silico ADMET Analysis
2.7. Molecular Target Prediction and Network Analysis
2.8. Pathway Enrichment Analysis (PEA) and Reactome Mining
3. Materials and Methods
3.1. Target Preparation
3.2. Database Preparation
3.3. Molecular Docking
3.4. Molecular Dynamics Simulations
3.5. MM-GBSA Binding Energy
3.6. Drug-Likeness Properties
3.7. In Silico ADMET Analysis
3.8. Protein Interaction Network Analyses
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound Name/Code | Origin/Usage b | Chemical Structure | Docking Score (kcal/mol) | Compound Name/Code | Origin/Usage b | Chemical Structure | Docking Score kcal/mol) | ||
---|---|---|---|---|---|---|---|---|---|
Conv. c | Exp. d | Conv. c | Exp. d | ||||||
XF7 | | −9.1 | −9.5 | T3D2324 | Industrial/workplace toxin | | −9.2 | −9.9 | |
T3D2489 | Insect toxin (Egyptian solitary wasp) | | −11.7 | −11.7 | T3D2680 | Synthetic compound (anticholesteremic agent) | | −9.8 | −9.9 |
T3D2672 | Marine toxin (Mytilus edulis) | | −11.3 | −11.6 | T3D2884 | Synthetic compound (antineoplastic agent) | | −9.8 | −9.9 |
T3D2378 | Industrial/workplace toxin | | −11.2 | −11.2 | T3D4082 | Plant toxin (Veratrum californicum) | | −9.8 | −9.8 |
T3D2807 | Synthetic compound (anti-anxiety agent) | | −10.9 | −10.9 | T3D2694 | Food toxin (antihypoparathyroid agent) | | −9.7 | −9.8 |
T3D2825 | Synthetic compound (antihypertensive agent) | | −10.9 | −10.9 | T3D2871 | Food toxin (antipsychotic agent) | | −9.7 | −9.8 |
T3D2874 | Synthetic compound (anti-allergic agent) | | −10.8 | −10.9 | T3D4050 | Plant toxin (Solanum chacoense) | | −9.6 | −9.8 |
T3D2938 | Synthetic compound (anti-allergic agent) | | −10.5 | −10.8 | T3D2536 | Animal toxin (B. rubescens, B. marinus) | | −9.6 | −9.8 |
T3D2913 | Synthetic compound (antipsychotic agent) | | −10.5 | −10.8 | T3D2933 | Synthetic compound (antipsychotic agent) | | −9.6 | −9.7 |
T3D4084 | Plant toxin (genus Veratrum) | | −10.2 | −10.6 | T3D4051 | Marine toxin (Tiostrea chilensis) | | −9.5 | −9.7 |
T3D2727 | Synthetic compound (antineoplastic agent) | | −10.1 | −10.5 | T3D2527 | Animal toxin (genus Dendrobates and genus Phyllobates) | | −9.5 | −9.7 |
T3D2460 | Synthetic compound (vasoconstrictor agent) | | −10.1 | −10.2 | T3D0233 | Synthetic compound (pesticide) | | −9.5 | −9.7 |
T3D2750 | Synthetic compound (vasoconstrictor agent) | | −10.0 | −10.2 | T3D2910 | Synthetic compound (cholinesterase inhibitor) | | −9.5 | −9.6 |
T3D2801 | Synthetic compound (psychotropic drug) | | −10.0 | −10.1 | T3D2863 | Synthetic compound (anti-HIV agent) | | −9.5 | −9.6 |
T3D4083 | Plant toxin (genus Veratrum) | | −9.9 | −10.1 | T3D2535 | Animal toxin (B. gargarizans) | | −9.4 | −9.6 |
T3D2939 | Synthetic compound (vasoconstrictor agent) | | −9.8 | −10.0 | T3D4232 | Bacterial toxin (cyanobacteria) | | −9.3 | −9. 6 |
T3D2143 | Industrial/workplace toxin | | −9.8 | −10.0 |
Compound Name/Code | milogP | TPSA | nON | nOHNH | Nrotb | MWt | %ABS |
---|---|---|---|---|---|---|---|
T3D2489 | 0.03 | 128.5 | 8 | 7 | 18 | 435.6 | 64.7% |
T3D2672 | 6.7 | 163.7 | 13 | 4 | 9 | 842.1 | 52.5% |
T3D2378 | 1.7 | 61.9 | 6 | 1 | 4 | 385.5 | 87.6% |
XF7 | 4.3 | 109.9 | 8 | 2 | 6 | 492.5 | 71.1% |
ADME Parameters | XF7 | T3D2489 | T3D2672 | T3D2378 |
---|---|---|---|---|
Absorption | ||||
Water solubility | −3.5 | −3.0 | −3.4 | −2.5 |
Caco2 permeability | 0.5 | −0.2 | −0.1 | 0.3 |
Intestinal absorption (human) | 93.5 | 47.6 | 56.7 | 95.0 |
Skin Permeability | −2.7 | −2.7 | −2.7 | −3.2 |
P-glycoprotein substrate | Yes | Yes | Yes | Yes |
P-glycoprotein I inhibitor | Yes | No | Yes | No |
P-glycoprotein II inhibitor | Yes | No | Yes | No |
Distribution | ||||
VDss (human) | 0.3 | 1.6 | 0.6 | 1.3 |
BBB permeability | −1.1 | −0.7 | −1.7 | 0.2 |
CNS permeability | −2.5 | −4.1 | −3.4 | −2.6 |
Metabolism | ||||
CYP2D6 substrate | No | No | No | No |
CYP3A4 substrate | Yes | No | Yes | Yes |
CYP1A2 inhibitior | No | No | No | No |
CYP2C19 inhibitior | Yes | No | No | No |
CYP2C9 inhibitior | Yes | No | No | No |
CYP2D6 inhibitior | No | No | No | No |
CYP3A4 inhibitior | Yes | No | No | No |
Excretion | ||||
Total Clearance | 0.8 | 1.4 | −0.1 | 0.8 |
Toxicity | ||||
AMES toxicity | No | No | No | No |
Max. tolerated dose (human) | 0.4 | 0.3 | −0.3 | −0.4 |
hERG I inhibitor | No | No | No | No |
hERG II inhibitor | Yes | Yes | No | Yes |
Oral Rat Acute Toxicity (LD50) | 3.3 | 2.7 | 2.8 | 2.4 |
Oral Rat Chronic Toxicity (LOAEL) | 1.1 | 3.1 | 2.7 | 0.7 |
Hepatotoxicity | Yes | Yes | Yes | Yes |
Skin Sensitisation | No | No | No | No |
T. Pyriformis toxicity | 0.3 | 0.3 | 0.3 | 0.6 |
Minnow toxicity | 2.4 | 2.2 | 0.9 | 4.7 |
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Ibrahim, M.A.A.; Abdelrahman, A.H.M.; Jaragh-Alhadad, L.A.; Atia, M.A.M.; Alzahrani, O.R.; Ahmed, M.N.; Moustafa, M.S.; Soliman, M.E.S.; Shawky, A.M.; Paré, P.W.; et al. Exploring Toxins for Hunting SARS-CoV-2 Main Protease Inhibitors: Molecular Docking, Molecular Dynamics, Pharmacokinetic Properties, and Reactome Study. Pharmaceuticals 2022, 15, 153. https://doi.org/10.3390/ph15020153
Ibrahim MAA, Abdelrahman AHM, Jaragh-Alhadad LA, Atia MAM, Alzahrani OR, Ahmed MN, Moustafa MS, Soliman MES, Shawky AM, Paré PW, et al. Exploring Toxins for Hunting SARS-CoV-2 Main Protease Inhibitors: Molecular Docking, Molecular Dynamics, Pharmacokinetic Properties, and Reactome Study. Pharmaceuticals. 2022; 15(2):153. https://doi.org/10.3390/ph15020153
Chicago/Turabian StyleIbrahim, Mahmoud A. A., Alaa H. M. Abdelrahman, Laila A. Jaragh-Alhadad, Mohamed A. M. Atia, Othman R. Alzahrani, Muhammad Naeem Ahmed, Moustafa Sherief Moustafa, Mahmoud E. S. Soliman, Ahmed M. Shawky, Paul W. Paré, and et al. 2022. "Exploring Toxins for Hunting SARS-CoV-2 Main Protease Inhibitors: Molecular Docking, Molecular Dynamics, Pharmacokinetic Properties, and Reactome Study" Pharmaceuticals 15, no. 2: 153. https://doi.org/10.3390/ph15020153