Theoretical insights into the binding interaction of Nirmatrelvir with SARS-CoV-2 Mpro mutants (C145A and C145S): MD simulations and binding free-energy calculation to understand drug resistance

Abstract

M^pro, the main protease and a crucial enzyme in SARS-CoV-2 is the most fascinating molecular target for pharmacological treatment and is also liable for viral protein maturation. For antiviral therapy, no drugs have been approved clinically to date. Targeting the M^pro with a compound having inhibitory properties against it can hinder viral replication. The therapeutic potential of the antiviral compound Nirmatrelvir (NMV) against SARS-CoV-2 M^pro was investigated using a systematic approach of molecular docking, MD simulations, and binding free energy calculation based on the MM-GBSA method. NMV, a covalent inhibitor with a recently revealed chemical structure, is a promising oral antiviral clinical candidate with significant in vitro anti-SARS-CoV-2 action in third-phase clinical trials. To explore the therapeutic ability and possible drug resistance, the M^pro system was studied for WT and two of its primary mutants (C145A & C145S). The protein-ligand (M^pro/NMV) complexes were further examined through long MD simulations to check the possible drug resistance in the mutants. To understand the binding affinity, the MM-GBSA method was applied to the M^pro/NMV complexes. Moreover, PCA analysis confirms the detachment of the linker region from the major domains in C145S and C145A mutants allowing for conformational alterations in the active-site region. Based on the predicted biological activities and binding affinities of NMV to WT and mutant (C145A & C145S) M^pro, it can be stipulated that NMV may have conventional potency to act as an anti-viral agent against WT M^pro, while the catalytic-dyad mutations may show substantial mutation-induced drug resistance.

Communicated by Ramaswamy H. Sarma

Keywords:

• COVID-19
• SARS-CoV-2 m^pro
• PF-07321332
• Nirmatrelvir
• drug resistance
• molecular dynamics simulation
• MM-GBSA

Acknowledgments

The authors sincerely acknowledge and thank Berhampur University for providing the infrastructure to study this work. All the authors thank the World Bank’s Odisha Higher Education Program for Excellence and Equity (OHEPEE), Department of Higher Education, Government of Odisha, which supports the Centre of Excellence on Bioprospecting of Ethno-pharmaceuticals of Southern Odisha, Berhampur University. The authors also thank Dr. Bibhuti Bhusan Parida, for certain technical assistance in the preparation of figures.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

BRM is supported through UGC-BSR Start-Up grant (F.30-484/2019(BSR)) by Govt. of India, and Science & Technology, Govt. of Odisha project (SCST-MISC-0061-2018-1288). PP is a BPRF (Biju Pattnaik Research Fellowship) awardee from Science & Technology (S&T), Govt. of Odisha, India (STBT-MISC-0007-2020-2047/ST).