Curcumin-Based Virtual Screening Identifies Inhibitors of SARS-CoV-2 Spike Protein and ACE2 Receptor Binding.

IF 1.9 4区 医学 Q3 CHEMISTRY, MEDICINAL
Timoteo Delgado-Maldonado, Luis D Gonzalez-Morales, Gilberto Vargas-Salas, Guadalupe Rojas-Verde, Eyra Ortíz-Pérez, Alma D Paz-Gonzalez, Gildardo Rivera
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引用次数: 0

Abstract

Background: To date, COVID-19 has caused over 772 million cases, with approximately 7 million deaths, according to the World Health Organization. Therefore, there is a need to develop new drugs to address the challenges posed by this disease.

Objective: To propose new antiviral agents based on the natural product curcumin as potential protein-protein interaction inhibitors between the SARS-CoV-2 spike receptor binding domain (RBD) and the ACE2 receptor.

Methods: A curcumin-based virtual screening was performed (Tanimoto coefficient= 0.9), and molecular docking analysis were carried out using the RBD as a receptor. Molecular dynamics (MD) using GROMACS were conducted for 120 ns. The SwissADME server was used to predict pharmacokinetics. To validate predictions, an in vitro enzyme assay measuring the relative inhibition of the interaction between the RBD and the ACE2 receptor was performed.

Results: More than 1300 ligands were evaluated through molecular docking. The docking results were analyzed, and the ligands were classified according to their score and profile of interactions with residues of the RBD of the SARS-CoV-2 S glycoprotein. The top ten with the best scores and interactions were selected to verify the commercial availability. The lead compound Cu-1 demonstrated significant interactions with the RBD and stability in MD simulations, was acquired and evaluated in vitro. Compound Cu-1 inhibited 36 ± 0.7 % the interaction between the SARSCoV- 2 spike and the ACE2 receptor. In addition, Cu-1 was shown to have an acceptable druglikeness and pharmacokinetic profile.

Conclusion: Curcumin provides a scaffold for identifying novel compounds with potential antiviral activity. Further studies on compound Cu-1 could yield on optimizing its structure to increase activity targeting the RBD of the S glycoprotein.

基于姜黄素的虚拟筛选鉴定SARS-CoV-2刺突蛋白和ACE2受体结合抑制剂
背景:根据世界卫生组织的数据,迄今为止,COVID-19已造成7.72亿多例病例,其中约700万人死亡。因此,有必要开发新药来应对这种疾病带来的挑战。目的:提出以天然产物姜黄素为基础的新型抗病毒药物,作为SARS-CoV-2刺突受体结合域(spike receptor binding domain, RBD)与ACE2受体之间潜在的蛋白-蛋白相互作用抑制剂。方法:以姜黄素为基础进行虚拟筛选(谷本系数= 0.9),以RBD为受体进行分子对接分析。用GROMACS进行了120 ns的分子动力学(MD)。使用SwissADME服务器预测药代动力学。为了验证预测,进行了一项体外酶测定,测量RBD和ACE2受体之间相互作用的相对抑制作用。结果:通过分子对接对1300多个配体进行了评价。对对接结果进行分析,并根据配体与sars - cov - 2s糖蛋白RBD残基的相互作用评分和谱进行分类。选择得分和交互最好的前十名来验证商业可用性。我们在体外获得并评估了铅化合物Cu-1与RBD的显著相互作用和MD模拟中的稳定性。化合物Cu-1对SARSCoV- 2与ACE2受体相互作用的抑制作用为36%±0.7%。此外,Cu-1被证明具有可接受的药物相似性和药代动力学特征。结论:姜黄素为鉴定具有潜在抗病毒活性的新化合物提供了一种框架。进一步研究化合物Cu-1可以优化其结构,提高其靶向S糖蛋白RBD的活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Medicinal Chemistry
Medicinal Chemistry 医学-医药化学
CiteScore
4.30
自引率
4.30%
发文量
109
审稿时长
12 months
期刊介绍: Aims & Scope Medicinal Chemistry a peer-reviewed journal, aims to cover all the latest outstanding developments in medicinal chemistry and rational drug design. The journal publishes original research, mini-review articles and guest edited thematic issues covering recent research and developments in the field. Articles are published rapidly by taking full advantage of Internet technology for both the submission and peer review of manuscripts. Medicinal Chemistry is an essential journal for all involved in drug design and discovery.
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