Coronaviruses are known to infect respiratory tract and intestine. These viruses possess highly conserved viral macro domain A1pp having adenosine diphosphate (ADP)-ribose binding and phosphatase activity sites. A1pp inhibits adenosine diphosphate (ADP)-ribosylation in the host and promotes viral infection and pathogenesis. We performed in silico screening of FDA approved drugs and nucleoside analogue library against the recently reported crystal structure of SARS-CoV-2 A1pp domain. Docking scores and interaction profile analyses exhibited strong binding affinity of eleven FDA approved drugs and five nucleoside analogues NA1 (−13.84), nadide (−13.65), citicholine (−13.54), NA2 (−12.42), and NA3 (−12.27). The lead compound NA1 exhibited significant hydrogen bonding and hydrophobic interaction at the natural substrate binding site. The root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent accessible surface (SASA), hydrogen bond formation, principle component analysis, and free energy landscape calculations for NA1 bound protein displayed stable complex formation in 100 ns molecular dynamics simulation, compared to unbound macro domain and natural substrate adenosine-5-diphosphoribose bound macro domain that served as a positive control. The molecular mechanics Poisson–Boltzmann surface area analysis of NA1 demonstrated binding free energy of −175.978 ± 0.401 kJ/mol in comparison to natural substrate which had binding free energy of −133.403 ± 14.103 kJ/mol. In silico analysis by modelling tool ADMET and prediction of biological activity of these compounds further validated them as putative therapeutic molecules against SARS-CoV-2. Taken together, this study offers NA1 as a lead SARS-CoV-2 A1pp domain inhibitor for future testing and development as therapeutics against human coronavirus.

已知冠状病毒会感染呼吸道和肠道。这些病毒具有高度保守的病毒宏结构域A1pp，具有二磷酸腺苷（ADP）-核糖结合和磷酸酶活性位点。A1pp抑制宿主中的二磷酸腺苷（ADP）-核糖基化并促进病毒感染和发病机理。我们针对最近报道的SARS-CoV-2 A1pp结构域的晶体结构，对FDA批准的药物和核苷类似物文库进行了计算机筛选。对接得分和相互作用谱分析显示了11种FDA批准药物和5种核苷类似物NA 1（−13.84），nadide（−13.65），citicholine（−13.54），NA 2（−12.42）和NA 3（− 12.27）。铅化合物NA图1显示了在天然底物结合位点的显着氢键和疏水相互作用。均方根偏差（RMSD），均方根波动（RMSF），回转半径（Rg），溶剂可及表面（SASA），氢键形成，主成分分析和NA 1结合蛋白的自由能态计算显示在100 ns的分子动力学模拟中，与未结合的宏结构域和天然底物腺苷5-二磷酸核糖结合的宏结构域（用作阳性对照）相比，稳定的复合物形成更为稳定。NA 1的泊松-玻尔兹曼表面积的分子力学分析与具有-133.403±14.103kJ / mol的结合底物的天然底物相比，具有-175.978±0.401kJ / mol的结合自由能。通过模拟工具ADMET进行的计算机分析以及对这些化合物的生物学活性的预测进一步验证了它们是针对SARS-CoV-2的推定治疗分子。两者合计，这项研究提供NA 1作为主要的SARS-CoV-2 A1pp结构域抑制剂，用于将来的测试和开发，作为抗人类冠状病毒的疗法。