Nagar Prinsa R, Gajjar Normi D, Dhameliya Tejas M
L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat 380009, India.
J Mol Struct. 2021 Dec 15;1246:131190. doi: 10.1016/j.molstruc.2021.131190. Epub 2021 Jul 26.
Severe acute respiratory syndrome has relapsed recently as novel coronavirus causing a life threat to the entire world in the absence of an effective therapy. To hamper the replication of the deadly SARS CoV-2 inside the host cells, systematic virtual screening of total 267,324 ligands from Asinex EliteSynergy and BioDesign libraries has been performed using AutoDock Vina against RdRp. The molecular modeling studies revealed the identification of twenty-one macrocyclic hits (-) with better binding energy than remdesivir (), marketed SARS CoV-2 inhibitor. Further, the analysis using rules for drug-likeness and their ADMET profile revealed the candidature of these hits due to superior oral bioavailability and druggability. Further, the MD simulation studies of top two hits ( and ) performed using GROMACS 2020.1 for 10 ns revealed their stability into the docked complexes. These results provide an important breakthrough in the design of macrocyclic hits as SARS CoV-2 RNA replicase inhibitor.
严重急性呼吸综合征最近再次出现，新型冠状病毒在缺乏有效治疗方法的情况下对全世界构成生命威胁。为了阻碍致命的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）在宿主细胞内的复制，已使用AutoDock Vina针对RNA依赖性RNA聚合酶（RdRp）对来自Asinex EliteSynergy和BioDesign库的总共267,324种配体进行了系统的虚拟筛选。分子建模研究表明，鉴定出了21种大环命中物（-），其结合能比已上市的SARS-CoV-2抑制剂瑞德西韦更好。此外，使用药物相似性规则及其药代动力学、药效学、药物代谢和毒性性质（ADMET）特征进行的分析表明，由于这些命中物具有卓越的口服生物利用度和可药用性，它们具有成为候选药物的资格。此外，使用GROMACS 2020.1对排名前两位的命中物（和）进行了10纳秒的分子动力学（MD）模拟研究，结果表明它们在对接复合物中具有稳定性。这些结果为设计作为SARS-CoV-2 RNA复制酶抑制剂的大环命中物提供了重要突破。
