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J Mol Struct ; 1246: 131124, 2021 Dec 15.
Article in English | MEDLINE | ID: covidwho-1313342


First emerged in late December 2019, the outbreak of novel severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) pandemic has instigated public-health emergency around the globe. Till date there is no specific therapeutic agent for this disease and hence, the world is craving to identify potential antiviral agents against SARS-CoV-2. The main protease (MPro) is considered as an attractive drug target for rational drug design against SARS-CoV-2 as it is known to play a crucial role in the viral replication and transcription. Teicoplanin is a glycopeptide class of antibiotic which is regularly used for treating Gram-positive bacterial infections, has shown potential therapeutic efficacy against SARS-CoV-2 in vitro. Therefore, in this study, a mechanistic insight of intermolecular interactions between teicoplanin and SARS-CoV-2 MPro has been scrutinized by molecular docking. Both monomeric and dimeric forms of MPro was used in docking involving blind as well as defined binding site based on the known inhibitor. Binding energies of teicoplanin-MPro complexes were estimated by Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) computations from docking and simulated trajectories. The dynamic and thermodynamics constraints of docked drug in complex with target proteins under specific physiological conditions was ascertained by all-atom molecular dynamics simulation of 100 ns trajectory. Root mean square deviation and fluctuation of carbon α chain justified the stability of the bound complex in biological environments. The outcomes of current study are supposed to be fruitful in rational design of antiviral drugs against SARS-CoV-2.

J Biomol Struct Dyn ; 40(6): 2851-2864, 2022 04.
Article in English | MEDLINE | ID: covidwho-1026871


Ivermectin (IVM) is a broad-spectrum antiparasitic agent, having inhibitory potential against wide range of viral infections. It has also been found to hamper SARS-CoV-2 replication in vitro, and its precise mechanism of action against SARS-CoV-2 is yet to be understood. IVM is known to interact with host importin (IMP)α directly and averts interaction with IMPß1, leading to the prevention of nuclear localization signal (NLS) recognition. Therefore, the current study seeks to employ molecular docking, molecular mechanics generalized Born surface area (MM-GBSA) analysis and molecular dynamics simulation studies for decrypting the binding mode, key interacting residues as well as mechanistic insights on IVM interaction with 15 potential drug targets associated with COVID-19 as well as IMPα. Among all COVID-19 targets, the non-structural protein 9 (Nsp9) exhibited the strongest affinity to IVM showing -5.30 kcal/mol and -84.85 kcal/mol binding energies estimated by AutoDock Vina and MM-GBSA, respectively. However, moderate affinity was accounted for IMPα amounting -6.9 kcal/mol and -66.04 kcal/mol. Stability of the protein-ligand complexes of Nsp9-IVM and IMPα-IVM was ascertained by 100 ns trajectory of all-atom molecular dynamics simulation. Structural conformation of protein in complex with docked IVM exhibited stable root mean square deviation while root mean square fluctuations were also found to be consistent. In silico exploration of the potential targets and their interaction profile with IVM can assist experimental studies as well as designing of COVID-19 drugs. Communicated by Ramaswamy H. Sarma.

COVID-19 Drug Treatment , Ivermectin , Antiviral Agents/chemistry , Humans , Ivermectin/pharmacology , Ivermectin/therapeutic use , Molecular Docking Simulation , SARS-CoV-2 , alpha Karyopherins