Identification of prospective covalent inhibitors for SARS-CoV-2 main protease using structure-based approach

Abstract

The rapid global spread of SARS-CoV-2 has recently caused havoc and forced the world into a state of the pandemic causing respiratory, gastrointestinal, hepatic, and neurologic diseases. It persistently, through mutation, develops into new variants of the virus that have appeared over time. As main protease (M^pro) is involved in proteolysis of two overlapping polyproteins pp1a and pp1ab to produce 16 non-structural proteins having a paramount factor in the virus replication that have a cysteine–histidine catalytic dyad. A computational approach, guiding a covalent docking as it offers higher potency, long duration of action and decreased drug resistance advantages over the conventional docking of the ligands on a catalytic dyad, is applied for SARS-CoV-2 main protease (M^pro) in this manuscript to divulge better molecules. M^pro active site contains Cys145 residue which act as a nucleophile and can donate its electron to an electrophilic molecule by interacting covalently. Furthermore, the ligand–protein complexes are allowed to simulate their dynamic studies to look into their time-based interaction stability and also, a parallel study of ADME properties for the hit molecules is also performed. Important insights from the studies revealed that the interactions are persistent and molecules may be considered for further optimization in clinical investigation.

Communicated by Ramaswamy H. Sarma.

Keywords:

• SARS-CoV-2
• main protease (M^pro)
• covalent docking
• MD simulations

Disclosure statement

The authors declare no competing interest.

Authors’ contributions

M. E. Sobhia (MES) designed the study. All the authors contributed to the computations, analysis and preparation of the manuscript.

Additional information

Funding

The authors thank the Director, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Ministry of Chemicals and fertilizers, Government of India for providing computational infrastructure to carry out this work. The financial assistance provided by the Department of Science and Technology (DST), New Delhi, and The Council of Scientific & Industrial Research (CSIR), New Delhi is duly acknowledged. This work was also supported by the Department of Biotechnology, Ministry of Science and Technology, Government of India under DBT project number—BT/PR40164/BTIS/137/17/2021.