Molecular docking and simulation studies of synthetic protease inhibitors against COVID-19: a computational study

COVID-19 is the most recent threat to global health. Many people preferred treatment in case of infection instead of vaccination. The inhibition of viral replication is a good strategy for the treatment of COVID-19 infection. 3CLpro and PLpro are two important viral proteases responsible for proteolysis, infection, and replication of the virus. Therefore, targeting of these two enzymes is an attractive way to deal with COVID-19. The aim of this study was to screen some synthetic protease inhibitors to determine an appropriate hit molecule against COVID-19 using molecular docking and molecular dynamic simulations. The strategy depends on docking existing synthetic compounds mostly HIV protease inhibitors against two COVID-19 proteases to identify promising drugs for the treatment of COVID-19. We used protein data bank to obtain the X-ray crystal structure of the most important COVID-19 proteases 3CL pro (PDB ID: 6M2N) and PL pro (PDB ID: 6WX4). In this conceptual context, an attempt has been made to suggest an in silico computational relationship between 50 synthetic protease inhibitors and COVID-19 proteases. Out of 50 screened compounds, the best docking scores were found for these five protease inhibitors BDBM7021, BDBM698, BDBM694, BDBM93239, BDBM700. A 100-ns MD simulation was carried out to assess the stability of COVID-19 proteases and inhibitors, revealing an average RMSD value of 0.7 and favorable binding free energy (MM-GBSA) for all complexes confirming their potency as powerful binders in the COVID-19 proteases’ binding pocket. Furthermore, the current results must be confirmed using in-<i>vitro</i> and in-<i>vivo</i> antiviral methods. Communicated by Ramaswamy H. Sarma

新型冠状病毒肺炎（COVID-19）是近期威胁全球公共健康的最严峻公共卫生事件。许多感染者更倾向于选择治疗手段而非疫苗接种。抑制病毒复制是治疗新型冠状病毒肺炎感染的有效策略。3CL蛋白酶（3CLpro）与PL蛋白酶（PLpro）是两类关键的病毒蛋白酶，参与病毒的蛋白水解、感染及复制过程。因此，以这两类酶为靶点是应对新型冠状病毒肺炎的极具吸引力的治疗思路。本研究旨在通过分子对接与分子动力学模拟技术，筛选合成蛋白酶抑制剂，以发掘可用于对抗新型冠状病毒肺炎的候选活性分子。本研究的策略为：将现有合成化合物（主要为人类免疫缺陷病毒（HIV）蛋白酶抑制剂）与两类新型冠状病毒肺炎蛋白酶进行分子对接，以期筛选出可用于治疗新型冠状病毒肺炎的潜在药物。本研究从蛋白质数据库（Protein Data Bank, PDB）中获取了两类关键新型冠状病毒肺炎蛋白酶的X射线晶体结构：3CL蛋白酶（3CLpro，PDB编号：6M2N）与PL蛋白酶（PLpro，PDB编号：6WX4）。本研究在上述研究框架下，尝试通过计算机模拟（in silico）计算方法，探究50种合成蛋白酶抑制剂与新型冠状病毒肺炎蛋白酶之间的相互作用关系。在50种被筛选的化合物中，BDBM7021、BDBM698、BDBM694、BDBM93239及BDBM700这5种蛋白酶抑制剂展现出最优的分子对接得分。本研究开展了时长为100纳秒的分子动力学（MD）模拟，以评估新型冠状病毒肺炎蛋白酶与抑制剂复合物的稳定性；结果显示，所有复合物的均方根偏差（RMSD）平均值为0.7，且结合自由能（MM-GBSA）表现优异，证实了这些抑制剂可有效结合至新型冠状病毒肺炎蛋白酶的结合口袋。此外，本研究所得结果尚需通过体外（in vitro）与体内（in vivo）抗病毒实验进一步验证。本文由Ramaswamy H. Sarma转交刊发。