Department of Chemistry, Graduate School of Science, Nagoya University, Furocho, Chikusa, Nagoya, 464-8601, Japan.
Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Furocho, Chikusa, Nagoya 464-8601, Japan.
Phys Chem Chem Phys. 2023 Aug 2;25(30):20597-20605. doi: 10.1039/d3cp01723k.
Nafamostat and camostat are known to inhibit the spike protein-mediated fusion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by forming a covalent bond with the human transmembrane serine protease 2 (TMPRSS2) enzyme. Previous experiments revealed that the TMPRSS2 inhibitory activity of nafamostat surpasses that of camostat, despite their structural similarities; however, the molecular mechanism of TMPRSS2 inhibition remains elusive. Herein, we report the energy profiles of the acylation reactions of nafamostat, camostat, and a nafamostat derivative by quantum chemical calculations using a combined molecular cluster and polarizable continuum model (PCM) approach. We further discuss the physicochemical relevance of their inhibitory activity in terms of thermodynamics and kinetics. Our analysis attributes the strong inhibitory activity of nafamostat to the formation of a stable acyl intermediate and its low activation energy during acylation with TMPRSS2. The proposed approach is also promising for elucidating the molecular mechanisms of other covalent drugs.
那法莫司他和卡莫司他通过与人类跨膜丝氨酸蛋白酶 2（TMPRSS2）酶形成共价键已知可抑制严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的刺突蛋白介导的融合。先前的实验表明，尽管结构相似，但那法莫司他对 TMPRSS2 的抑制活性超过了卡莫司他；然而，TMPRSS2 抑制的分子机制仍不清楚。在此，我们通过使用组合分子簇和极化连续体模型（PCM）方法的量子化学计算报告了那法莫司他、卡莫司他和那法莫司他衍生物的酰化反应的能量分布。我们进一步讨论了它们在热力学和动力学方面抑制活性的物理化学相关性。我们的分析将那法莫司他的强抑制活性归因于与 TMPRSS2 酰化过程中形成稳定的酰基中间体及其低活化能。该方法还有望阐明其他共价药物的分子机制。
