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

Abstract

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.

SARS-CoV-2 E protein: Pathogenesis and potential therapeutic development

“…Yadav et al demonstrated by computational methods that CDC and UDC can stably bind to the transmembrane domain of SARS-CoV-2 E protein through hydrogen bond and other interactions to form a thermodynamically stable complex, in which T30 residue is the key residue to bind to CDC and UDC. [87] CDC and UDC can also destroy the hydrogen bond between adjacent chains to loose the structure of E protein pentamer and allow a large number of CDC molecules to enter the membrane. In conclusion, these two drugs can inhibit the survival of SARS-CoV-2 virus by destroying the structure of E protein and promoting the entry of inhibitors into virus-infected cells.…”