Promising inhibitors of nsp2 of CHIKV using molecular docking and temperature-dependent molecular dynamics simulations

Infection due to the Chikungunya virus (CHIKV) has taken the life of lots of people; and researchers are working to find the vaccine or promisng drug candidates against this viral infection. In this work, the authors have designed one component reaction based on the thia-/oxa-azolidineone and created a library of 2000 molecules based on the product obtained. Further, the compounds were screened through the docking using iGemdock against the non-structural protein 2 (nsp2) of CHIKV. Molecular docking gives the binding energy (BE) or energy for the formation of the complex between the designed compound and nsp2 of CHIKV; and CMPD222 gave the lowest energy. This is based on the energy obtained from van der Waal’s interaction, hydrogen bonding and electrostatic instructions. Further, molecular dynamics simulations (MDS) of nsp2 of CHIKV with and without screened compound (222) were performed to validate the docking results and the change in free energy for the formation of the complex is −10.8327 kcal/mol. To explore the potential of CMPD222, the MDS of the CMPD222-nsp2 of CHIKV were performed at different temperatures (325, 350, 375 and 400 K) to understand the inhibition of the protease. MM-GBSA calculations were performed to determined change in entropy, change in enthalpy and change in free energy to understand the inhibition. Maximum inhibition of nsp2 of CHIKV with CMPD222 is observed at 375 K with a change in free energy of −19.3754 kcal/mol. Communicated by Ramaswamy H. Sarma

基孔肯雅病毒（Chikungunya virus, CHIKV）感染已造成大量人员死亡，研究人员正致力于开发针对该病毒感染的疫苗及有前景的候选药物。本研究中，作者基于硫杂/氧杂氮杂环戊酮设计了单组分反应，并基于所得产物构建了包含2000个分子的化合物库。随后，研究人员使用iGemdock分子对接软件，针对基孔肯雅病毒非结构蛋白2（non-structural protein 2, nsp2）对所有化合物进行了筛选。分子对接可得到设计化合物与CHIKV nsp2形成复合物的结合能（binding energy, BE），其中化合物CMPD222的结合能最低，该结合能基于范德华相互作用、氢键作用与静电相互作用计算得到。为验证分子对接结果，研究人员分别对结合与未结合筛选得到的化合物222的CHIKV nsp2进行了分子动力学模拟（molecular dynamics simulations, MDS），结果显示该复合物的自由能变化为-10.8327 kcal/mol。为探究CMPD222的抗病毒潜力，研究人员在325、350、375及400 K四种不同温度下，对CHIKV CMPD222-nsp2复合物开展了分子动力学模拟，以解析其对蛋白酶的抑制机制。通过MM-GBSA计算，研究人员得到了熵变、焓变与自由能变化，以进一步阐明其抑制作用机制。在375 K时，CMPD222对CHIKV nsp2的抑制效果最强，此时复合物的自由能变化为-19.3754 kcal/mol。由Ramaswamy H. Sarma转交。