Program in Biotechnology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol BS8 1TS, UK.
Phys Chem Chem Phys. 2019 Jul 10;21(27):14945-14956. doi: 10.1039/c9cp02377a.
Zika virus (ZIKV) infection has become a global public health problem, associated with microcephaly in newborns and Guillain-Barré syndrome in adults. Currently, there are no commercially available anti-ZIKV drugs. The viral protease NS2B/NS3, which is involved in viral replication and maturation, is a potential drug target. Peptidomimetic aldehyde inhibitors bind covalently to the catalytic S135 of the NS3 protease. Here, we apply hybrid quantum mechanics/molecular mechanics (QM/MM) free-energy simulations at the PDDG-PM3/ff14SB level to investigate the inhibition mechanism of the ZIKV protease by a dipeptidyl aldehyde inhibitor (acyl-KR-aldehyde). The results show that proton transfer from the catalytic S135 to H51 occurs in concert with nucleophilic addition on the aldehyde warhead by S135. The anionic covalent complex between the dipeptidyl aldehyde and the ZIKV protease is analogous to the tetrahedral intermediate for substrate hydrolysis. Spontaneous protonation by H51 forms the hemiacetal. In addition, we use correlated ab initio QM/MM potential energy path calculations at levels up to LCCSD(T)/(aug)-cc-pVTZ to obtain accurate potential energy profiles of the reaction, which also support a concerted mechanism. These results provide detailed insight into the mechanism of ZIKV protease inhibition by a peptidyl aldehyde inhibitor, which will guide in the design of inhibitors.
寨卡病毒（ZIKV）感染已成为全球公共卫生问题，与新生儿小头畸形和成人吉兰-巴雷综合征有关。目前，尚无市售的抗寨卡病毒药物。病毒蛋白酶 NS2B/NS3 参与病毒复制和成熟，是一个潜在的药物靶点。肽模拟醛抑制剂通过共价键与 NS3 蛋白酶的催化 S135 结合。在这里，我们应用混合量子力学/分子力学（QM/MM）自由能模拟在 PDDG-PM3/ff14SB 水平上研究二肽醛抑制剂（酰基-KR-醛）对寨卡病毒蛋白酶的抑制机制。结果表明，催化 S135 向 H51 的质子转移与 S135 上的醛弹头的亲核加成同时发生。二肽醛与寨卡病毒蛋白酶之间的阴离子共价复合物类似于底物水解的四面体中间体。H51 的自发质子化形成半缩醛。此外，我们使用相关的从头算 QM/MM 势能路径计算，最高可达 LCCSD(T)/(aug)-cc-pVTZ，以获得反应的准确势能曲线，这也支持协同机制。这些结果提供了对肽醛抑制剂抑制寨卡病毒蛋白酶机制的详细了解，这将指导抑制剂的设计。
