Abstract
The outbreak of the recent coronavirus (SARS-CoV-2), which causes a severe pneumonia infection, first identified in Wuhan, China, imposes significant risks to public health. Around the world, researchers are continuously trying to identify small molecule inhibitors or vaccine candidates by targeting different drug targets. The SARs-CoV-2 macrodomain-I, which helps in viral replication and hijacking the host immune system, is also a potential drug target. Hence, this study targeted viral macrodomain-I by using drug similarity, virtual screening, docking and re-docking approaches. A total of 64,043 compounds were screened, and potential hits were identified based on the docking score and interactions with the key residues. The top six hits were subjected to molecular dynamics simulation and Free energy calculations and repeated three times each. The per-residue energy decomposition analysis reported that these compounds significantly interact with Asp22, Ala38, Asn40, Val44, Phe144, Gly46, Gly47, Leu127, Ser128, Gly130, Ile131, Phe132 and Ala155 which are the critical active site residues. Here, we also used ADPr as a positive control to compare our results. Our results suggest that our identified hits by using such a complicated computational pipeline could inhibit the SARs-CoV-2 by targeting the macrodomain-1. We strongly recommend the experimental testing of these compounds, which could rescue the host immune system and could help to contain the disease caused by SARs-CoV-2.Communicated by Ramaswamy H. Sarma.
Keywords: Macrodomain-I; SARs-CoV-2; drug similarity; free energy; immune system.
【저자키워드】 SARS-CoV-2, immune system, Macrodomain-I, drug similarity, free energy, 【초록키워드】 public health, coronavirus, Infection, risk, Virtual screening, docking, molecular dynamics, immune system, Molecular dynamics simulation, free energy, Replication, Free energy calculations, Viral, outbreak, viral replication, Wuhan, drug target, vaccine candidate, small molecule, targets, severe pneumonia, Critical, Small molecule inhibitors, Interaction, Analysis, similarity, active site, approaches, residue, Compound, help, macrodomain, host immune system, residues, vaccine candidates, these compounds, positive control, docking score, ADPr, researcher, repeated, Wuhan, China, identify, caused, significantly, reported, inhibit, the disease, screened, in viral, these compound, cause, small molecule inhibitor, 【제목키워드】 drug, immune, molecular, similarity, Compound, Host, structure-based screening,