Abstract
Severe acute respiratory syndrome-coronavirus2 (SARS-CoV2), a new coronavirus has emerged in Wuhan city of China, December 2019 causing pneumonia named Coronavirus disease-19 (COVID-19), which has spread to the entire world. By January 2021, number of confirmed cumulative cases crossed ∼104 million worldwide. Till date, no effective treatment or drug is available for this virus. Availability of X-ray structures of SARS-CoV2 main protease (Mpro) provides the potential opportunity for structure-based drug designing. Here, we have made an attempt to do computational drug design by targeting main protease of SARS-CoV2. High-throughput virtual screening of million molecules and natural compounds databases were performed followed by docking. After that, the protein-ligand complexes were optimized and rescoring of binding energies were accomplished through molecular dynamics simulation and Molecular mechanics Poisson Boltzmann surface area approaches, respectively. In addition, conformational effect of various ligands on protein was also examined through essential dynamics simulation. Three compounds namely ZINC14732869, ZINC19774413, and ZINC19774479 were finally filtered that displayed better binding affinities than N3 (known) inhibitor and formed conformationally stable complexes. Hence, the current study features the potential novel inhibitors against main protease of SARS-CoV2 which might provide an effective therapeutic strategy against COVID-19. Communicated by Ramaswamy H. Sarma
Highlights
Emergence of SARS (Severe acute respiratory syndrome coronavirus) in 2002-03 fromGuangdong, China and MERS (Middle East respiratory syndrome coronavirus) in 2012-13 from Jeddah, Saudi Arabia toll up to ~10617 cases with a mortality of ~1640 as per WHO (World Health Organization) by January, 20201-2
main protease (Mpro) consists of 3 domains wherein domain I (8-101 amino acids long) and domain II (102-184 amino acids long) have an antiparallel β-barrels
Domains II and III is connected by large loop that provide site for substrate binding
Summary
Emergence of SARS (Severe acute respiratory syndrome coronavirus) in 2002-03 fromGuangdong, China and MERS (Middle East respiratory syndrome coronavirus) in 2012-13 from Jeddah, Saudi Arabia toll up to ~10617 cases with a mortality of ~1640 as per WHO (World Health Organization) by January, 20201-2. CoV is spherical in shape with spikes projecting on its outer surface, which help it to adhere on the host cell, followed by structural changes in the host cell that allow virus to enter into the host[5] Upon entry, it started utilising host replication machinery for replication and accelerated its copy numbers in the cytoplasm. The ability of coronavirus to adapt itself into new environment through mutation and recombination, fuel its evolution and constructed various strains that are highly pathogenic in nature[7] These strains act as causative agent and lead to gastrointestinal, central nervous system and other diseases in addition to respiratory syndrome[8]. Mammals are to be an ideal host for Alphacoronavirus and Betacoronavirus while an Aves hosts for Gammacoronavirus and Deltacoronavirus[9]
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