Abstract

Drug repurposing is an apt choice to combat the currently prevailing global threat of COVID-19, caused by SARS-Cov2in absence of any specific medication/vaccine. The present work employs state of art computational methods like homology modelling, molecular docking and molecular dynamics simulations to evaluate the potential of two widely used surfactant drugs namely chenodeoxycholate(CDC) and ursodeoxycholate (UDC), to bind to the envelope protein of SARS-Cov2(SARS-Cov2-E).The monomeric unit of SARS-Cov2-E was modelled from a close homologue (>90% sequence identity) and a pentameric assembly was modelled using symmetric docking, followed by energy minimization in a DPPC membrane environment. The minimized structure was used to generate best scoring SARS-Cov2-E–CDC/UDC complexes through blind docking. These complexes were subjected to 230 ns molecular dynamics simulations in triplicates in a DPPC membrane environment. Comparative analyses of structural 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 with the transmembrane-channelresidues.T30 was observed to be a key residue for CDC/UDC binding. CDC/UDC binding affected the H-bonding pattern between adjacent monomeric chains, slackening the compact transmembrane region of SARS-Cov2-E. Additionally, the polar functional groups of CDC/UDC facilitated entry of a large number of water molecules into the channel. These observations suggest CDC/UDC as potential candidates to hinder the survival of SARS-Cov2 by disrupting the structure of SARS-Cov2-E and facilitating the entry of solvents/polar inhibitors inside the viral cell.

Communicated by Ramaswamy H. Sarma

 抽象的

在没有任何特定药物/疫苗的情况下，药物再利用是应对当前由 SARS-Cov2 引起的全球流行的 COVID-19 威胁的适当选择。目前的工作采用同源建模、分子对接和分子动力学模拟等最先进的计算方法来评估两种广泛使用的表面活性剂药物即鹅去氧胆酸盐（CDC）和熊去氧胆酸盐（UDC）与SARS-Cov2包膜蛋白结合的潜力(SARS-Cov2-E)。SARS-Cov2-E 的单体单元是根据紧密同源物（> 90% 序列同一性）建模的，并使用对称对接对五聚体组装进行建模，然后在 DPPC 膜环境中进行能量最小化。最小化的结构用于通过盲对接生成最佳评分的 SARS-Cov2-E–CDC/UDC 复合物。这些复合物在 DPPC 膜环境中进行了三次 230 ns 分子动力学模拟。 MD 轨迹的结构特性和分子相互作用谱的比较分析表明，CDC 和 UDC 都可以通过氢键、水桥和与跨膜通道残基的疏水接触稳定地与 SARS-Cov2-E 结合。是 CDC/UDC 结合的关键残基。 CDC/UDC 结合影响相邻单体链之间的氢键模式，使 SARS-Cov2-E 的紧凑跨膜区域松弛。此外，CDC/UDC的极性官能团促进大量水分子进入通道。这些观察结果表明，CDC/UDC 是通过破坏 SARS-Cov2-E 的结构并促进溶剂/极性抑制剂进入病毒细胞内部来阻碍 SARS-Cov2 存活的潜在候选者。

拉马斯瓦米·萨尔马 (Ramaswamy H. Sarma) 通讯