Bioinformatics, DBT-National Institute of Animal Biotechnology (NIAB), Hyderabad 500032, India.
Amity Institute of Biotechnology, Amity University Mumbai, Navi Mumbai 410206, India.
Molecules. 2022 Jan 26;27(3):801. doi: 10.3390/molecules27030801.
The human population is still facing appalling conditions due to several outbreaks of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) virus. The absence of specific drugs, appropriate vaccines for mutants, and knowledge of potential therapeutic agents makes this situation more difficult. Several 1, 2, 4-triazolo [1, 5-a] pyrimidine (TP)-derivative compounds were comprehensively studied for antiviral activities against RNA polymerase of HIV, HCV, and influenza viruses, and showed immense pharmacological interest. Therefore, TP-derivative compounds can be repurposed against the RNA-dependent RNA polymerase (RdRp) protein of SARS-CoV-2. In this study, a meta-analysis was performed to ensure the genomic variability and stability of the SARS-CoV-2 RdRp protein. The molecular docking of natural and synthetic TP compounds to RdRp and molecular dynamic (MD) simulations were performed to analyse the dynamic behaviour of TP compounds at the active site of the RdRp protein. TP compounds were also docked against other non-structural proteins (NSP1, NSP2, NSP3, NSP5, NSP8, NSP13, and NSP15) of SARS-CoV-2. Furthermore, the inhibition potential of TP compounds was compared with Remdesivir and Favipiravir drugs as a positive control. Additionally, TP compounds were analysed for inhibitory activity against SARS-CoV RdRp protein. This study demonstrates that TP analogues (monomethylated triazolopyrimidine and essramycin) represent potential lead molecules for designing an effective inhibitor to control viral replication. Furthermore, in vitro and in vivo studies will strengthen the use of these inhibitors as suitable drug candidates against SARS-CoV-2.
由于严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）病毒的几次爆发，人类仍面临着可怕的情况。缺乏针对突变体的特定药物、适当的疫苗和潜在治疗药物的知识，使得情况更加困难。几种 1、2、4-三唑并[1,5-a]嘧啶（TP）衍生物化合物已被广泛研究用于针对 HIV、HCV 和流感病毒的 RNA 聚合酶的抗病毒活性，并显示出巨大的药理学兴趣。因此，TP 衍生物化合物可以重新用于对抗 SARS-CoV-2 的 RNA 依赖性 RNA 聚合酶（RdRp）蛋白。在这项研究中，进行了荟萃分析以确保 SARS-CoV-2 RdRp 蛋白的基因组变异性和稳定性。对天然和合成 TP 化合物与 RdRp 的分子对接以及分子动力学（MD）模拟进行了研究，以分析 TP 化合物在 RdRp 蛋白活性部位的动态行为。TP 化合物也对接了 SARS-CoV-2 的其他非结构蛋白（NSP1、NSP2、NSP3、NSP5、NSP8、NSP13 和 NSP15）。此外，将 TP 化合物的抑制潜力与瑞德西韦和法匹拉韦药物作为阳性对照进行了比较。此外，还分析了 TP 化合物对 SARS-CoV RdRp 蛋白的抑制活性。本研究表明，TP 类似物（单甲基化三唑嘧啶和 essramycin）代表了设计有效抑制剂以控制病毒复制的潜在先导分子。此外，体外和体内研究将加强这些抑制剂作为针对 SARS-CoV-2 的合适药物候选物的使用。
