Abstract

The COVID-19 pandemic is an ongoing global health emergency caused by a newly discovered coronavirus SARS-CoV-2. The entire scientific community across the globe is working diligently to tackle this unprecedented challenge. In silico studies have played a crucial role in the current situation by expediting the process of identification of novel potential chemotypes targeting the viral receptors. In this study, we have made efforts to identify molecules that can potentially inhibit the SARS-CoV-2 main protease (M^pro) using the high-resolution crystal structure of SARS-CoV-2 M^pro. The SARS-CoV-2 M^pro has a large flexible binding pocket that can accommodate various chemically diverse ligands but a complete occupation of the binding cavity is necessary for efficient inhibition and stability. We augmented glide three-tier molecular docking protocol with water thermodynamics to screen molecules obtained from three different compound libraries. The diverse hits obtained through docking studies were scored against generated WaterMap to enrich the quality of results. Five molecules were selected from each compound library on the basis of scores and protein-ligand complementarity. Further MD simulations on the proposed molecules affirm the stability of these molecules in the complex. MM-GBSA results and intermolecular hydrogen bond analysis also confirm the thermodynamic stability of proposed molecules. This study also presumably steers the structure determination of many ligand-main protease complexes using x-ray diffraction methods.

Communicated by Ramaswamy H. Sarma

摘要

COVID-19大流行是由新发现的冠状病毒SARS-CoV-2引起的持续不断的全球卫生紧急情况。全球各地的整个科学界都在努力应对这一前所未有的挑战。在计算机领域，研究加速了针对病毒受体的新型潜在化学型的鉴定过程，在当前形势下发挥了至关重要的作用。在这项研究中，我们已经作出努力来识别可以潜在地抑制SARS-CoV的-2主要蛋白酶分子（M^亲使用SARS-CoV的-2的高分辨率晶体结构M）^亲。SARS-CoV-2 M^专业版具有较大的柔性结合袋，可以容纳各种化学上不同的配体，但要有效抑制和稳定，必须完全占据结合腔。我们使用水热力学增强了滑行三层分子对接方案，以筛选从三个不同化合物库中获得的分子。通过对接研究获得的各种命中结果将针对生成的WaterMap进行评分，以丰富结果的质量。基于分数和蛋白质-配体互补性，从每个化合物库中选择五个分子。拟议分子的进一步MD模拟证实了这些分子在复合物中的稳定性。MM-GBSA结果和分子间氢键分析也证实了所提出分子的热力学稳定性。

由Ramaswamy H.Sarma沟通