Pharmacophore based virtual screening, molecular docking, molecular dynamics and MM-GBSA approach for identification of prospective SARS-CoV-2 inhibitor from natural product databases

Abstract

COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily appeared in Wuhan, China, in December 2019. At present, no proper therapy and vaccinations are available for the disease, and it is increasing day by day with a high mortality rate. Pharmacophore based virtual screening of the selected natural product databases followed by Glide molecular docking and dynamics studies against SARS-CoV-2 main protease was investigated to identify potential ligands that may act as inhibitors. The molecules SN00293542 and SN00382835 revealed the highest docking score of 214.57 and 212.42 kcal/mol, respectively, when compared with the co-crystal ligands of PDB-6Y2F (O6K) and 6W63 (X77) of the SARS-CoV-2 M pro. To further validate the interactions of top scored molecules SN00293542 and SN00382835, molecular dynamics study of 100 ns was carried out. This indicated that the protein-ligand complex was stable throughout the simulation period, and minimal backbone fluctuations have ensued in the system. Post-MM-GBSA analysis of molecular dynamics data showed free binding energy-71.7004 1/2 7.98, 256.811/2 7.54 kcal/mol, respectively. The computational study identified several ligands that may act as potential inhibitors of SARS-CoV-2 M pro. The top-ranked molecules SN00293542, and SN00382835 occupied the active site of the target, the main protease like that of the co-crystal ligand. These molecules may emerge as a promising ligands against SARS-CoV-2 and thus needs further detailed investigations.

In silico exploration of lignin peroxidase for unraveling the degradation mechanism employing lignin model compounds

“…The selected protein (LiP) was prepared by exploiting the protein preparation wizard (pre-processed, optimized, and minimized), through the addition of hydrogen atoms, hydrogen bond optimization, and verifying the protonation states of HIS, GLN, and ASN amino acid residues (Schrödinger release 2020-3: Glide, Schrödinger, LLC, New York, NY, 2020). 82,88 Energy minimization was achieved with the help of a default constraint of 0.3 A RMSD and applying the OPLS 2005 force eld. 85 Extra precision Glide docking Grid preparation.…”

Perceiving SARS-CoV2 Mpro and PLpro dual inhibitors from pool of recognized antiviral compounds of endophytic microbes: an in-silico simulation study

“…PLpro protein of SARS-CoV2 (PDB ID: 7CMD) co-crystalized form with GRL0617 and Mpro of SARS-CoV2 (PDB ID: 6W63) co-crystalized form with X77 were retrieved from protein databank (PDB) [19][20][21] . Here, GRL0617 and X77 are the known inhibitors for respective proteins and were used as reference.…”

“…Coronavirus disease 19 (COVID- 19) is a new SARS-CoV2 linked disease that manifests as a range of clinical signs going from asymptomatic, minor influenza like manifestations to acute respiratory distress, pneumonia, and demise 1,2 . COVID-19 pandemic shown up over eighteen months prior and flipped around our lives.…”

In silico exploration of phytoconstituents from Phyllanthus emblica and Aegle marmelos as potential therapeutics against SARS-CoV-2 RdRp

“…The docked complexes were solvated using an implicit solvent model in a cubic box of 10 Å spacing [60]. The solvated systems were neutralized with counter ions, and physiological salt concentration was maintained to 0.15 M [73]. All the systems were set up at constant NPT [N(number), P(pressure), T(time)] ensemble [74] with atmospheric pressure (1.013 bar), and a constant temperature of 300k over 100ns simulation [75].…”