利用全面的药物再利用和分子对接方法预测 SARS-CoV-2 的 RNA 依赖性 RNA 聚合酶的潜在抑制剂。

Prediction of potential inhibitors for RNA-dependent RNA polymerase of SARS-CoV-2 using comprehensive drug repurposing and molecular docking approach.

机构信息

Department of Genetic Engineering & Biotechnology, Shahjalal University of Science & Technology, Sylhet 3114, Bangladesh.

Department of Genetic Engineering & Biotechnology, Jashore University of Science & Technology, Jashore, Bangladesh; Center for Bioinformatics, Universitat Des Saarlandes, Saarbrucken, Germany.

出版信息

Int J Biol Macromol. 2020 Nov 15;163:1787-1797. doi: 10.1016/j.ijbiomac.2020.09.098. Epub 2020 Sep 17.

Abstract

The pandemic prevalence of COVID-19 has become a very serious global health issue. Scientists all over the world have been seriously attempting in the discovery of a drug to combat SARS-CoV-2. It has been found that RNA-dependent RNA polymerase (RdRp) plays a crucial role in SARS-CoV-2 replication, and thus could be a potential drug target. Here, comprehensive computational approaches including drug repurposing and molecular docking were employed to predict an effective drug candidate targeting RdRp of SARS-CoV-2. This study revealed that Rifabutin, Rifapentine, Fidaxomicin, 7-methyl-guanosine-5'-triphosphate-5'-guanosine and Ivermectin have a potential inhibitory interaction with RdRp of SARS-CoV-2 and could be effective drugs for COVID-19. In addition, virtual screening of the compounds from ZINC database also allowed the prediction of two compounds (ZINC09128258 and ZINC09883305) with pharmacophore features that interact effectively with RdRp of SARS-CoV-2, indicating their potentiality as effective inhibitors of the enzyme. Furthermore, ADME analysis along with analysis of toxicity was also undertaken to check the pharmacokinetics and drug-likeness properties of the two compounds. Comparative structural analysis of protein-inhibitor complexes revealed that the amino acids Y32, K47, Y122, Y129, H133, N138, D140, T141, S709 and N781 are crucial for drug surface hotspot in the RdRp of SARS-CoV-2.

摘要

新冠疫情的流行已成为一个非常严重的全球健康问题。全世界的科学家一直在认真尝试发现一种药物来对抗 SARS-CoV-2。研究发现,RNA 依赖性 RNA 聚合酶(RdRp)在 SARS-CoV-2 复制中起着至关重要的作用,因此可能是一个潜在的药物靶点。在这里,我们采用了包括药物重定位和分子对接在内的综合计算方法,来预测针对 SARS-CoV-2 RdRp 的有效药物候选物。本研究表明,利福布丁、利福平、非达霉素、7-甲基鸟苷-5'-三磷酸-5'-鸟苷和伊维菌素与 SARS-CoV-2 RdRp 具有潜在的抑制相互作用,可能是治疗 COVID-19 的有效药物。此外,对 ZINC 数据库中的化合物进行虚拟筛选,也预测了两种具有药效基团特征的化合物(ZINC09128258 和 ZINC09883305),它们与 SARS-CoV-2 RdRp 有效相互作用,表明它们作为该酶有效抑制剂的潜力。此外,还进行了 ADME 分析和毒性分析,以检查两种化合物的药代动力学和类药性特征。蛋白-抑制剂复合物的比较结构分析表明,Y32、K47、Y122、Y129、H133、N138、D140、T141、S709 和 N781 氨基酸对 SARS-CoV-2 RdRp 的药物表面热点至关重要。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9606/7495146/41b0f7f8b58c/gr1_lrg.jpg

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