Drug Repurposing Studies Targeting SARS-nCoV2: An Ensemble Docking Approach on Drug Target 3C-like Protease (3CLpro)

Abstract

<p>The COVID-19 pandemic has been responsible for several deaths worldwide. The causative agent behind this disease is the Severe Acute Respiratory Syndrome – novel Coronavirus 2 (SARS-nCoV2). SARS-nCoV2 belongs to the category of RNA viruses. The main protease, responsible for the cleavage of the viral polyprotein is considered as one of the hot targets for treating COVID-19. Earlier reports suggest the use of HIV anti-viral drugs for targeting the main protease of SARS-CoV, which caused SARS in the year 2002-03. Hence, drug repurposing approach may prove to be useful in targeting the main protease of SARS-nCoV2. The high-resolution crystal structure of 3CL<sup>pro</sup> (main protease) of SARS-nCoV2 (PDB ID: 6LU7) was used as the target. The Food and Drug Administration (FDA) approved and SWEETLEAD database of drug molecules were screened. The apo form of the main protease was simulated for a cumulative of 150 ns and 10 μs open source simulation data was used, to obtain conformations for ensemble docking. The representative structures for docking were selected using RMSD-based clustering and Markov State Modeling analysis. This ensemble docking approach for main protease helped in exploring the conformational variation in the drug binding site of the main protease leading to efficient binding of more relevant drug molecules. The drugs obtained as best hits from the ensemble docking possessed anti-bacterial and anti-viral properties. Small molecules with these properties may prove to be useful to treat symptoms exhibited in COVID-19. This <i>in-silico</i> ensemble docking approach would support identification of potential candidates for repurposing against COVID-19.</p>

Drug repurposing and computational modeling for discovery of inhibitors of the main protease (Mpro) of SARS-CoV-2

“…79 These residues are mainly part of the S1 subsite (Asn142, Cys145 e Glu166) and S2 (His41 e Gln189), in addition, studies by Koulgi and collaborators suggest that the inhibitory effect is observed when interactions with these key residues occur at the active site of the enzyme. 80 Apart from remdesivir, application of darunavir against Covid-19 should be highlighted, especially since it has been studied as a possible treatment for SARS-CoV-2, and due to in vitro evidence that supports its ability to ght the disease. 81…”

The Pharmaceuticals Using for COVID-19 Patients and in Silico Natural Product Studies about COVID-19

“…Cefuroxime listed 8th and was concluded to attach with affinity energy of -9.2kcal/mol with an IC50 of 2.09mM [118]. Koulgi and co-workers [123] applying both a "direct docking" and an "ensemble docking" approach. The direct docking was a simple docking of promising medicines against the crystal structure of Mpro while the altogether coming included docking against variations in conformation of the active pocket of Mpro, which generally cause to perfect outcomes.…”