Abstract
The main protease (3CLpro) is one of the essential components of the SARS-CoVs viral life cycle, which makes it an interesting target for overpowering these viruses. Although many covalent and noncovalent inhibitors have been designed to inhibit this molecular target, none have gained FDA approval as a drug. Because of the high rate of COVID-19 pandemic development, in addition to laboratory research, we require in silico methods to accelerate rational drug design. The unbinding pathways of two SARS-CoV and SARS-CoV-2 3CLpro noncovalent inhibitors with the PDB IDs: 3V3M, 4MDS, 6W63, 5RF7 were explored from a comparative perspective using unbiased molecular dynamics (UMD) simulations. We uncovered common weak points for selected inhibitors that could not interact significantly with a binding pocket at specific residues by all their fragments. So water molecules entered the free binding S regions and weakened protein-inhibitor fundamental interactions gradually. N142, G143, and H163 are the essential residues, which cause key protein-ligand interactions in the binding pocket. We believe that these results will help design new potent inhibitors against SARS-CoV-2.
Highlights
Severe Acute Respiratory Syndrome (SARS) occurred in Guangdong Province of China in 2002–2003, which was caused by SARS-CoV-1, a coronavirus of 2b β-coronavirus [1]
One of the selected compounds, ML188 (PDB ID 3V3M) with an IC50 of 4.11 μM [14], were simulated in 3 replicas, and the complete unbinding processes occurred at the times of 60, 40, and 37 ns (Fig 3A)
By putting together the atomic details of the unbinding pathways of selected inhibitors except inhibitor 4 in PDB ID 5RF7, one significant common weakness point was observed at various times in all replicas
Summary
Severe Acute Respiratory Syndrome (SARS) occurred in Guangdong Province of China in 2002–2003, which was caused by SARS-CoV-1, a coronavirus of 2b β-coronavirus [1]. A novel coronavirus (2019-nCoV) was identified in Wuhan, China, in late 2019 for the first time [2]. This virus, which was scientifically named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected many people in different parts of the world with its high prevalence power and caused the COVID-19 pandemic with symptoms including fever, cough, and fatigue [3, 4]. After two years, according to the World Health Organization(WHO) reports, 4,777,503 people have lost their lives all around the world (Updated on October 03, 2021) [5].
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