Quantitative structure-activity relationships, molecular docking and molecular dynamics simulations reveal drug repurposing candidates as potent SARS-CoV-2 main protease inhibitors

2021 ◽  
pp. 1-18
Author(s):  
Anacleto Silva de Souza ◽  
Robson Francisco de Souza ◽  
Cristiane Rodrigues Guzzo
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Protease Inhibitors ◽  
Drug Repurposing ◽  
Quantitative Structure ◽  
Structure Activity ◽  
Main Protease ◽  
Quantitative Structure Activity Relationships ◽  
Dynamics Simulations

scholarly journals Virtual Repurposing of Ursodeoxycholate and Chenodeoxycholate as Lead Candidates Against SARS-Cov2-Envelope Protein: A Molecular Dynamics Investigation

2020 ◽  
Author(s):  
Reena Yadav ◽  
chinmayee choudhury ◽  
Yashwant Kumar ◽  
Alka Bhatia
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Envelope Protein ◽  
Homology Modelling ◽  
Protein A ◽  
Drug Repurposing ◽  
Dynamics Simulations ◽  
Global Threat ◽  
Polar Functional Groups

Drug repurposing is an apt choice to combat the currently prevailing global threat of COVID-19, caused by SARS-Cov2 in absence of any specific medication/vaccine. The present work attempts to computationally evaluate binding affinities and effect of two widely used surfactant drugs i.e. chenodeoxycholate (CDC) and ursodeoxycholate (UDC) with the envelope protein of SARS-Cov2 (SARS-Cov2-E) using homology modelling, molecular docking and molecular dynamics simulations. A good quality homo-pentameric structure of SARS-Cov2-E was modelled from its homologue with more than 90% sequence identity followed by symmetric docking. The pentameric structure was embedded in a DPPC membrane and subsequently energy minimized. The minimized structure was used for blind molecular docking of CDC and UDC to obtain the best scoring SARS-Cov2-E–CDC/UDC complexes, which were subjected to 230ns molecular dynamics simulations in triplicates in DPPC membrane environment. Comparative analyses of structural and enthalpic properties and molecular interaction profiles from the MD trajectories revealed that, both CDC and UDC could stably bind to SARS-Cov2-E through H-bonds, water-bridges and hydrophobic contacts in the transmembraneresidues.T30 was observed to be a key residue for CDC/UDC binding. The polar functional groups of the bound CDC/UDC facilitated entry of a large number of water molecules into the channel and affected the H-bonding pattern between adjacent monomeric chains, loosening the compact transmembrane region of SARS-Cov2-E. These observations suggest the potential of CDC/UDC as repurposed candidates to hinder the survival of SARS-Cov2 by disrupting the structure of SARS-Cov2-E and facilitate entry of solvents/polar inhibitors inside the viral cell.

scholarly journals Exploring the Potency of Nigella sativa Seed in Inhibiting SARS-CoV-2 Main Protease Using Molecular Docking and Molecular Dynamics Simulations

2021 ◽  
Vol 21 (5) ◽  
pp. 1252
Author(s):  
Ari Hardianto ◽  
Muhammad Yusuf ◽  
Ika Wiani Hidayat ◽  
Safri Ishmayana ◽  
Ukun Mochammad Syukur Soedjanaatmadja
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Global Economy ◽  
Nigella Sativa ◽  
Scientific Information ◽  
Dynamics Simulation ◽  
Lipinski’S Rule ◽  
Main Protease ◽  
Dynamics Simulations

Coronavirus disease (COVID-19) is a pandemic burdening the global economy. It is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Black cumin (Nigella sativa) seed may contain antivirals for the disease since it was reported to inhibit the human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Main protease (Mpro) is a vital protein for viral replication and a promising target for COVID-19 drug development. Hence, in this study, we intended to uncover the potency of N. sativa seed as the natural source of inhibitors for SARS-CoV-2 Mpro. We collected secondary metabolites in N. sativa seed through a literature search and employed Lipinski’s rule of five as the initial filter. Subsequently, virtual screening campaigns using a molecular docking method were performed, with N3 inhibitor and leupeptin as reference ligands. The top hits were analyzed further using a molecular dynamics simulation approach. Molecular dynamics simulations showed that binding affinities of nigellamine A2 and A3 to Mpro are comparable to that of leupeptin, with median values of -43.9 and -36.2 kcal mol–1, respectively. Ultimately, this study provides scientific information regarding N. sativa seeds’ potency against COVID-19 and helps direct further wet experiments.

scholarly journals Virtual Repurposing of Ursodeoxycholate and Chenodeoxycholate as Lead Candidates Against SARS-Cov2-Envelope Protein: A Molecular Dynamics Investigation

2020 ◽  
Author(s):  
Reena Yadav ◽  
chinmayee choudhury ◽  
Yashwant Kumar ◽  
Alka Bhatia
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Envelope Protein ◽  
Homology Modelling ◽  
Protein A ◽  
Drug Repurposing ◽  
Dynamics Simulations ◽  
Global Threat ◽  
Polar Functional Groups

Drug repurposing is an apt choice to combat the currently prevailing global threat of COVID-19, caused by SARS-Cov2 in absence of any specific medication/vaccine. The present work attempts to computationally evaluate binding affinities and effect of two widely used surfactant drugs i.e. chenodeoxycholate (CDC) and ursodeoxycholate (UDC) with the envelope protein of SARS-Cov2 (SARS-Cov2-E) using homology modelling, molecular docking and molecular dynamics simulations. A good quality homo-pentameric structure of SARS-Cov2-E was modelled from its homologue with more than 90% sequence identity followed by symmetric docking. The pentameric structure was embedded in a DPPC membrane and subsequently energy minimized. The minimized structure was used for blind molecular docking of CDC and UDC to obtain the best scoring SARS-Cov2-E–CDC/UDC complexes, which were subjected to 230ns molecular dynamics simulations in triplicates in DPPC membrane environment. Comparative analyses of structural and enthalpic properties and molecular interaction profiles from the MD trajectories revealed that, both CDC and UDC could stably bind to SARS-Cov2-E through H-bonds, water-bridges and hydrophobic contacts in the transmembraneresidues.T30 was observed to be a key residue for CDC/UDC binding. The polar functional groups of the bound CDC/UDC facilitated entry of a large number of water molecules into the channel and affected the H-bonding pattern between adjacent monomeric chains, loosening the compact transmembrane region of SARS-Cov2-E. These observations suggest the potential of CDC/UDC as repurposed candidates to hinder the survival of SARS-Cov2 by disrupting the structure of SARS-Cov2-E and facilitate entry of solvents/polar inhibitors inside the viral cell.

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