Cysteine focused covalent inhibitors against the main protease of SARS-CoV-2

Abstract

In viral replication and transcription, the main protease (Mpro) of SARS-CoV-2 plays an important role and appears to be a vital target for drug design. In Mpro, there is a Cys–His catalytic dyad, and ligands that interact with the Cys145 assumed to be an effective approach to inhibit the Mpro. In this study, approximately 1400 cysteine-focused ligands were screened to identify the best candidates that can act as potent inhibitors against Mpro. Our results show that the selected ligands strongly interact with the key Cys145 and His41 residues. Covalent docking was performed for the selected candidates containing the acrylonitrile group, which can form a covalent bond with Cys145. All atoms molecular dynamics (MD) simulation was performed on the selected four inhibitors including L1, L2, L3 and L4 to validate the docking interactions. Our results were also compared with a control ligand, α-ketoamide (11r). Principal component analysis on structural and energy data obtained from the MD trajectories shows that L1, L3, L4 and α-ketoamide (11r) have structural similarity with the apo-form of the Mpro. Quantitative structure-activity relationship method was employed for pattern recognition of the best ligands, which discloses that ligands containing acrylonitrile and amide warheads can show better performance. ADMET analysis displays that our selected candidates appear to be safer inhibitors. Our combined studies suggest that the best cysteine focused ligands can help to design an effective lead drug for COVID-19 treatment.

Communicated by Ramaswamy H. Sarma

Graphical Abstract

Keywords:

• Cysteine focused inhibitors
• Covid-19
• main protease
• molecular docking
• molecular dynamics

Acknowledgements

We are grateful to our donors who supported to build a computational platform (http://grc-bd.org/donate/). The authors like to acknowledge the World Academy of Science (TWAS) to purchase High-Performance Computer for performing molecular dynamics simulation. Authors like to thank Prof. Philip S. Low of Purdue University for providing access to use covalent docking in Schrödinger program.

Disclosure statement

No potential conflict of interest was reported by the authors.