ABSTRACT
The COVID-19 disease is caused by a new strain of the coronavirus family (SARS-CoV-2), and it has affected at present millions of people all over the world. The indispensable role of the main protease (Mpro) in viral replication and gene expression makes this enzyme an attractive drug target. Therefore, inhibition of SARS-CoV-2 Mpro as a proposition to halt virus ingression is being pursued by scientists globally. Here we carried out a study with two objectives: the first being to perform comparative protein sequence and 3D structural analysis to understand the effect of 12 point mutations on the active site. Among these, two mutations, viz., Ser46 and Phe134, were found to cause a significant change at the active sites of SARS-CoV-2. The Ser46 mutation present at the entrance of the S5 subpocket of SARS-CoV-2 increases the contribution of other two hydrophilic residues, while the Phe134 mutation, present in the catalytic cysteine loop, can cause an increase in catalytic efficiency of Mpro by facilitating fast proton transfer from the Cys145 to His41 residue. It was observed that active site remained conserved among Mpro of both SARS-CoVs, except at the entrance of the S5 subpocket, suggesting sustenance of substrate specificity. The second objective was to screen the inhibitory effects of three different data sets (natural products, coronaviruses main protease inhibitors, and FDA-approved drugs) using a structure-based virtual screening approach. A total of 73 hits had a combo score >2.0. Eight different structural scaffold classes were identified, such as one/two tetrahydropyran ring(s), dipeptide/tripeptide/oligopeptide, large (approximately 20 atoms) cyclic peptide, and miscellaneous. The screened hits showed key interactions with subpockets of the active site. Further, molecular dynamics studies of selected screened compounds confirmed their perfect fitting into the subpockets of the active site. This study suggests promising structures that can fit into the SARS-CoV-2 Mpro active site and also offers direction for further lead optimization and rational drug design.
Subject(s)
Antiviral Agents/chemistry , COVID-19 Drug Treatment , Coronavirus 3C Proteases/chemistry , Mutant Proteins/chemistry , SARS-CoV-2/drug effects , Viral Protease Inhibitors/chemistry , Amino Acid Sequence , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Catalytic Domain , Coronavirus 3C Proteases/metabolism , Databases, Factual , Drug Design , Humans , Hydrophobic and Hydrophilic Interactions , Models, Molecular , Mutant Proteins/metabolism , Protein Conformation , Structure-Activity Relationship , Viral Protease Inhibitors/metabolism , Viral Protease Inhibitors/pharmacologyABSTRACT
Epidemically increased evidence reveals that the link between the 2019-nCoV and other similar strain of coronaviruses circulating in bats and specifically the Rhinopodous bat sub-species. These sub-species are ample and widely present in Southern China, Middle East Africa and Europe. Recent studies show that more than 500 CoV have been identified in bats in China. The Center for Diseases Control and Prevention and the World Health Organization maintains a website that is updated frequently with new cases of MERS-CoV infection. As per WHO Situation report 16th, 24,554 number of cases confirmed globally out of which 99.22% cases from china. A new coronavirus (2019-nCoV) is causing respiratory syndrome mostly in Hubei Province, China. Corona Virus spread over 24 countries including Japan, India, Korea, and other countries 2019-CoV infection vary from mild, moderate or severe illness; the later includes severe pneumonia, ARDS, sepsis and septic shock. There are two diagnostic tests for coronavirus infection i.e. molecular test and serology test. In this review article there are the various recent cases of the patients that are suffering from the corona virus, the outcome of these studies is that corona virus infection is an epidemic disease which affects Central Nervous System (CNS).