Abstract

Coronaviruses are RNA viruses that infect varied species including humans. TMPRSS2 is gateway for SARS CoV-2 entry into the host cell. It causes proteolytic activation of spike protein and discharge of the peptide into host cell. The TMPRSS2 inhibition could be one of the approaches to stop the viral entry, therefore, interaction pattern and binding energies for Fisetin and TMPRSS2 have been explored in the present study. TMPRSS2 peptide was used for homology modelling and then for further study. Molecular docking score and MMGBSA Binding energy of Fisetin was better than Nafamostat, a known inhibitor of TMPRSS2. Post docking MM-GBSA free energy for Fisetin and Nafamostat was −42.78 and −21.11 kcal/mol, respectively. Fisetin forms H bond with Val 25, His 41, Lys 42, Lys 45, Glu 44, Ser186. Nafamostat formed H bonds with Lys 85, Asp 90, Asp 203. RMSD plots of TMPRSS2, TMPRSS2-Fisetin and TMPRSS2-Nafamostat complex showed stable profile with very small fluctuation during entire simulation of 150 ns. Significant decrease in TMPRSS2-Fisetin and TMPRSS2-Nafamostat complex fluctuation occurred around His 41, Glu 44, Gly 136, Ser 186 in RMSF study. During simulation Fisetin interaction was observed with residues Val 25, His 41, Glu 44, Lys 45, Lys 87, Gly 136, Gln 183, Ser 186 likewise interaction of Nafamostat with Lys 85, Asp 90, Asn 163, Asp 203 and Ser 205. Post simulation MM-GBSA free energy was found to be −51.87 ± 4.3 and −48.23 ± 4.39 kcal/mol for TMPRSS2 with Fisetin and Nafamostat, respectively.

Communicated by Ramaswamy H. Sarma

 抽象的

冠状病毒是 RNA 病毒，可感染包括人类在内的多种物种。 TMPRSS2 是 SARS CoV-2 进入宿主细胞的门户。它引起刺突蛋白的蛋白水解激活并将肽释放到宿主细胞中。 TMPRSS2 抑制可能是阻止病毒进入的方法之一，因此，本研究已探讨 Fisetin 和 TMPRSS2 的相互作用模式和结合能。 TMPRSS2肽用于同源建模，然后用于进一步研究。 Fisetin 的分子对接评分和 MMGBSA 结合能优于 Nafamostat（一种已知的 TMPRSS2 抑制剂）。 Fisetin 和 Nafamostat 的对接后 MM-GBSA 自由能分别为 -42.78 和 -21.11 kcal/mol。非瑟酮与 Val 25、His 41、Lys 42、Lys 45、Glu 44、Ser186 形成 H 键。 Nafamostat 与 Lys 85、Asp 90、Asp 203 形成 H 键。TMPRSS2、TMPRSS2-Fisetin 和 TMPRSS2-Nafamostat 复合物的 RMSD 图显示在 150 ns 的整个模拟过程中稳定的轮廓，波动非常小。 RMSF 研究中，TMPRSS2-Fisetin 和 TMPRSS2-Nafamostat 复合物波动显着降低，发生在 His 41、Glu 44、Gly 136、Ser 186 周围。在模拟过程中，观察到非瑟酮与残基 Val 25、His 41、Glu 44、Lys 45、Lys 87、Gly 136、Gln 183、Ser 186 的相互作用，同样 Nafamostat 与 Lys 85、Asp 90、Asn 163、Asp 203 和 Ser 205 的相互作用发现含有 Fisetin 和 Nafamostat 的 TMPRSS2 的后模拟 MM-GBSA 自由能分别为 -51.87 ± 4.3 和 -48.23 ± 4.39 kcal/mol。

拉马斯瓦米·萨尔马 (Ramaswamy H. Sarma) 通讯