Iterated Virtual Screening-Assisted Antiviral and Enzyme Inhibition Assays Reveal the Discovery of Novel Promising Anti-SARS-CoV-2 with Dual Activity
Abstract
:1. Introduction
2. Results
2.1. Rational Lead Discovery of Potential Anti-SARS-CoV-2
2.2. Candidate Election by Enumerated Structure Ligand Designer
2.3. Two Candidate Compounds (M3 and M5) Showed Promising Anti-SARS-CoV-2 Activity In Vitro
2.4. Compound M3 Possesses Dual Inhibition Activity against SARS-CoV-2 by Targeting Both the Viral and Human Proteases
2.5. Molecular Docking Indicated the Binding Efficiency of M3 with SARS-CoV-2 Mpro and TMPRSS2 Protease
2.6. MD Simulation Confirmed the Stability of M3 Complex with the Target Enzymes, SARS-CoV-2 Mpro and Human TMPRSS2
2.7. WaterMap Analysis Showed the Pronounced Efficacy of M3
2.8. Adsorption of M3 Compound on ZnO NPs Enhanced the Efficiency against SARS-CoV-2
3. Discussion
4. Conclusions
5. Experimental Section
5.1. Material
5.2. Computational Studies
5.2.1. Protein Preparation
5.2.2. Ligand Preparation
5.2.3. Grid Generation
5.2.4. Molecular Docking
5.2.5. Induced Docking Fit (IDF)
5.2.6. Molecular Dynamics Simulation
5.2.7. WaterMap Analysis
5.2.8. PathFinder R-Group Enumeration
5.2.9. Ligand Designer
5.2.10. R-Group Analysis
5.3. Chemistry
5.4. In Vitro Evaluation of Anti-SARS-CoV-2 Activity
5.5. Cell Viability Assay
5.6. Main Protease (Mpro) Assay
5.7. Furin Protease Assay
5.8. TMPRSS2 Fluorogenic Assay
5.9. Preparation of Compound-Loaded ZnO Nanoparticles
5.10. Characterization of Compound-ZnO Nanoparticles
5.11. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Compound | Docking Score with | |
---|---|---|
MPRO | TMPRSS2 | |
M1 | −9.97 | −8.11 |
M2 | −8.16 | −8.53 |
M3 | −8.79 | −9.81 |
M4 | −9.67 | −9.32 |
M5 | −7.37 | −6.32 |
Compound 13 | −7.01 | −9.86 |
Compound | Moiety | Interaction | Amino Acid Residue |
---|---|---|---|
M1 | NH N of oxadiazole Phenyl ring | H-bond H-bond pi-pi stacking bond Hydrophobic bond | Glu-166 Asn-142 His-41 His-41, Met-49, Cys-145, Met-165 and Pro-168 |
M2 | NH2 | 2H-bonds Hydrophobic bond | Phe-140 and Glu-166 His-41, Met-49, Cys-145, Met-165 and Gln-189 |
M3 | NH2 NH N pyridyl moiety and CH | 2H-bonds H-bond H-bond Hydrophobic bond | Cys-44 and Thr-25 Asn-142 Glu-166 Met-49, Cys-44, Glu-166 and Met-165 |
M4 | NH2 Cl | 2- H-bonds Halogen bond Hydrophobic bond | Glu-166 and Phe-140 Gln-192 Met-49, Glu-166, Cys-145, Met-165, Gln-189, Gln-192 and Pro-168 |
M5 | NH2 | 2H-bonds Hydrophobic bond | Glu-166 and Phe-140 Cys-44, His-41, Met-49, Gln-189 and Pro-168 |
Compound 13 | Phenolic OH NH2 NH2 N Phenolic OH Phenyl ring and CH | H-bond H-bond H-bond pi-pi stacking bond Hydrophobic bond | Glu-166 Phe-140 Thr-26 His-40 Met-44, Cys-44 and Met-165. |
Compound | Moiety | Interaction | Amino Acid Residue |
---|---|---|---|
M1 | NH N | H-bond H-bond Hydrophobic bond | Gln-192 Ser-195 Arg-41, Cys-219 and Tyr-228 |
M2 | NH2 NH | H-bond H-bond Hydrophobic bond | Gln-192 Ser-214 Tyr-36, Arg-41, Gln-192, Val-213 and Cys-219 |
M3 | 2-NH N of 4-pyridyl moiety N pyridinyl moiety and CH | 2H-bonds H-bond H-bond Hydrophobic bond | Ser-214 Arg-41 Glu-218 His-57, Arg-41 and Cys-219 and Cys-42 |
M4 | NH2 Cl N | 3-H-bonds 3-Halogen bond H-bond Hydrophobic bond | His-57, Ser-214, Gln-192 Ala-220, Ser-214, Ser-39 Arg-41 Arg-41, Val-213, Cys-219 and Tyr-228 |
M5 | OCH3 NH | H-bond H-bond Hydrophobic bond | Arg-41 Gln-192 Arg-41, Tyr-149, Ala-190, Val-213 and Cys-219 |
Compound 13 | Phenolic OH NH2 NH2 N Phenolic OH Phenyl ring and CH | H-bond H-bond H-bond H-bond H-bond Hydrophobic bond | His-40 Gln-192 Ser-214 Arg-41 Glu-218 Arg-41, Ala-190, Val-213, Cys-42 and Trp-36 |
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Hamdy, R.; Fayed, B.; Mostafa, A.; Shama, N.M.A.; Mahmoud, S.H.; Mehta, C.H.; Nayak, Y.; M. Soliman, S.S. Iterated Virtual Screening-Assisted Antiviral and Enzyme Inhibition Assays Reveal the Discovery of Novel Promising Anti-SARS-CoV-2 with Dual Activity. Int. J. Mol. Sci. 2021, 22, 9057. https://doi.org/10.3390/ijms22169057
Hamdy R, Fayed B, Mostafa A, Shama NMA, Mahmoud SH, Mehta CH, Nayak Y, M. Soliman SS. Iterated Virtual Screening-Assisted Antiviral and Enzyme Inhibition Assays Reveal the Discovery of Novel Promising Anti-SARS-CoV-2 with Dual Activity. International Journal of Molecular Sciences. 2021; 22(16):9057. https://doi.org/10.3390/ijms22169057
Chicago/Turabian StyleHamdy, Rania, Bahgat Fayed, Ahmed Mostafa, Noura M. Abo Shama, Sara Hussein Mahmoud, Chetan Hasmukh Mehta, Yogendra Nayak, and Sameh S. M. Soliman. 2021. "Iterated Virtual Screening-Assisted Antiviral and Enzyme Inhibition Assays Reveal the Discovery of Novel Promising Anti-SARS-CoV-2 with Dual Activity" International Journal of Molecular Sciences 22, no. 16: 9057. https://doi.org/10.3390/ijms22169057