PDF(Pubmed)
Abstract：
SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. For the virus to enter the host cell, its spike (S) protein binds to the ACE2 receptor, and the transmembrane protease serine 2 (TMPRSS2) cleaves the binding for the fusion. As part of the research on COVID-19 treatments, several Casiopeina-analogs presented here were looked at as TMPRSS2 inhibitors. Using the DFT and conceptual-DFT methods, it was found that the global reactivity indices of the optimized molecular structures of the inhibitors could be used to predict their pharmacological activity. In addition, molecular docking programs (AutoDock4, Molegro Virtual Docker, and GOLD) were used to find the best potential inhibitors by looking at how they interact with key amino acid residues (His296, Asp 345, and Ser441) in the catalytic triad. The results show that in many cases, at least one of the amino acids in the triad is involved in the interaction. In the best cases, Asp435 interacts with the terminal nitrogen atoms of the side chains in a similar way to inhibitors such as nafamostat, camostat, and gabexate. Since the copper compounds localize just above the catalytic triad, they could stop substrates from getting into it. The binding energies are in the range of other synthetic drugs already on the market. Because serine protease could be an excellent target to stop the virus from getting inside the cell, the analyzed complexes are an excellent place to start looking for new drugs to treat COVID-19.
摘要：
SARS-CoV-2是导致COVID-19大流行的病毒。为了让病毒进入宿主细胞，它的刺突（S）蛋白与ACE2受体结合，和跨膜蛋白酶丝氨酸2(TMPRSS2)切割融合的结合。作为COVID-19治疗研究的一部分，本文提出的几种Casiopeina类似物被视为TMPRSS2抑制剂。使用DFT和概念DFT方法，已发现，优化的抑制剂分子结构的整体反应性指数可用于预测其药理活性。此外,分子对接程序(AutoDock4，Molegro虚拟Docker，和GOLD）用于通过观察它们如何与催化三联体中的关键氨基酸残基（His296，Asp345和Ser441）相互作用来找到最佳的潜在抑制剂。结果表明，在许多情况下，三联体中的至少一个氨基酸参与相互作用。在最好的情况下,Asp435与侧链的末端氮原子以类似于nafamostat等抑制剂的方式相互作用，camostat,还有Gabexate.由于铜化合物位于催化三联体上方，他们可以阻止底物进入其中。结合能在已经在市场上的其他合成药物的范围内。因为丝氨酸蛋白酶可能是阻止病毒进入细胞内部的绝佳靶标，分析的复合物是开始寻找治疗COVID-19的新药的绝佳场所。
