Computational Determination of Potential Inhibitors of SARS-CoV-2 Main Protease

Abstract

The novel coronavirus (SARS-CoV-2) has infected several million people and caused thousands of deaths worldwide since December 2019. As the disease is spreading rapidly all over the world, it is urgent to find effective drugs to treat the virus. The main protease (Mpro) of SARS-CoV-2 is one of the potential drug targets. Therefore, in this context, we used rigorous computational methods, including molecular docking, fast pulling of ligand (FPL), and free energy perturbation (FEP), to investigate potential inhibitors of SARS-CoV-2 Mpro. We first tested our approach with three reported inhibitors of SARS-CoV-2 Mpro, and our computational results are in good agreement with the respective experimental data. Subsequently, we applied our approach on a database of ∼4600 natural compounds, as well as 8 available HIV-1 protease (PR) inhibitors and an aza-peptide epoxide. Molecular docking resulted in a short list of 35 natural compounds, which was subsequently refined using the FPL scheme. FPL simulations resulted in five potential inhibitors, including three natural compounds and two available HIV-1 PR inhibitors. Finally, FEP, the most accurate and precise method, was used to determine the absolute binding free energy of these five compounds. FEP results indicate that two natural compounds, cannabisin A and isoacteoside, and an HIV-1 PR inhibitor, darunavir, exhibit a large binding free energy to SARS-CoV-2 Mpro, which is larger than that of 13b, the most reliable SARS-CoV-2 Mpro inhibitor recently reported. The binding free energy largely arises from van der Waals interaction. We also found that Glu166 forms H-bonds to all of the inhibitors. Replacing Glu166 by an alanine residue leads to ∼2.0 kcal/mol decreases in the affinity of darunavir to SARS-CoV-2 Mpro. Our results could contribute to the development of potential drugs inhibiting SARS-CoV-2.

Protease targeted COVID-19 drug discovery and its challenges: Insight into viral main protease (Mpro) and papain-like protease (PLpro) inhibitors

“…Currently, scientific community are largely focused in the screening of – (i) FDA-approved drug databases, (ii) clinical trials molecules and/or (iii) previously reported coronavirus inhibitors 9 . In silico virtual screening (VS) techniques are proficient to explore CoV protease inhibitors 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 . Yu and co-workers 40 reported the computational screening and findings with regard to potential binding luteolin and other natural compounds against Mpro.…”

“…Vast amount of in silico VS studies against SARS-CoV-2 Mpro has been reported over past months 26-30, 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 . As the detailed description on the molecular modeling studies is out of Scope for this current communication, readers interested in learning more about recent molecular modeling studies to identify probable CoV protease inhibitors are directed to mentioned references 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72...…”

Molecular Basis of SARS-CoV-2 Infection and Rational Design of Potential Antiviral Agents: Modeling and Simulation Approaches

“… 240 In this case, ritonavir, lopinavir, and darunavir (anti-HIV drugs) were considered, and it was finally suggested that darunavir should be more selective for recognizing PLpro instead of 3CLpro. Nevertheless, additional docking studies suggest that darunavir could also be a suitable choice to bind 3CLpro, 241 , 242 highlighting the relevance of this particular anti-HIV drug as a potential anti-COVID-19 clinical drug.…”

Drug Binding Dynamics of the Dimeric SARS-CoV-2 Main Protease, Determined by Molecular Dynamics Simulation

“…Furthermore, it has been recently reported that nelfinavir had anti-SARS-CoV-2 activity, as demonstrated in a cell-based experimental assay [12,13]. In addition, other HIV protease inhibitors such as indinavir, darunavir, and saquinavir, have been proposed as drug candidates against SARS-CoV-2 M pro , using computational studies [14][15][16][17][18]. These HIV protease inhibitors are repurposed drug candidates, some of which are already being tested in clinical trials.…”