Discovery of Potential Compounds Against SARS-CoV-2 Based on 3CLpro/RdRp Dual-target: An In silico Approach

IF 1.2 4区医学 Q4 CHEMISTRY, MEDICINAL

Letters in Drug Design & Discovery Pub Date : 2023-11-01 DOI:10.2174/1570180819666220818145647

Jiaojiao Li, Lin Zhu, Zheng Qin, Zhengfu Li, Xun Gao, Jing Ji, Jinyang Shen

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引用次数: 0

Abstract

Background: The COVID-19 outbreak is a serious concern and has caused a great loss to the global economy. Therefore, COVID-19 has become an urgent public health problem. Although new vaccines and small molecule drugs are now available, these prevention and treatment methods cannot completely control the epidemic due to the constant mutation of SARS-CoV-2. Targeting 3CLpro/RdRp is expected to develop drugs that are not susceptible to the mutation of SARS-COV-2, and it will also have a certain effect on the coronavirus that may appear in the future. Objective: This study aimed to find small molecules against SARS-CoV-2 with research potential and provide relevant data for the rational development of anti-SARS-COV-2 drugs. Methods: Targeting 3CLpro/RdRp, using Shards database (120,000 natural small molecule compounds) in the ZINC database, adopting a step-by-step screening strategy, and taking Lopinavir, Indinavir, and Molnupiravir as screening criteria was done. Moreover, the top scoring compounds were screened using rigid docking, and molecular dynamics simulation and ADME prediction were performed. Finally, the molecules with better scores were screened out. Results: After molecular docking with 3CLpro as the target, 3207 compounds meeting the screening criteria were obtained. After applying Lipinski's rule of five for drug property screening, 1825 compounds that met the criteria were obtained. After molecular docking with RdRp as the target, ZINC04259665 has a good docking score. According to molecular dynamics simulation results, ZINC04259665 is stable in combination with 3CLpro/RdRp. ADME prediction shows that ZINC04259665 has good druggability. Conclusion: Using 3CLpro/RdRp targets and then using a step-by-step strategy to screen the compound with the highest score through molecular dynamics simulation and ADME prediction, it was found that ZINC04259665 has good development potential and can be used as a follow-up hit compound for research. In addition, the data obtained provide relevant information for the rational development of anti- SARS-COV-2 drugs.

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基于3CLpro/RdRp双靶点的潜在抗SARS-CoV-2化合物的发现:一种计算机方法

背景:新冠肺炎疫情令人严重关切，给全球经济造成巨大损失。因此，新冠肺炎已成为一个紧迫的公共卫生问题。虽然现在有了新的疫苗和小分子药物，但由于SARS-CoV-2的不断变异，这些预防和治疗方法并不能完全控制疫情。以3CLpro/RdRp为靶点，有望开发出对SARS-COV-2突变不敏感的药物，对未来可能出现的冠状病毒也会有一定的作用。目的:寻找具有研究潜力的抗SARS-CoV-2小分子，为抗SARS-CoV-2药物的合理开发提供相关数据。方法:以3CLpro/RdRp为靶点，利用ZINC数据库中的Shards数据库(12万种天然小分子化合物)，采用分步筛选策略，以Lopinavir、Indinavir、Molnupiravir为筛选标准。采用刚性对接筛选得分最高的化合物，并进行分子动力学模拟和ADME预测。最后，筛选出得分较高的分子。结果:以3CLpro为靶点进行分子对接，得到符合筛选标准的化合物3207个。应用Lipinski的五法则进行药物性质筛选，得到1825个符合标准的化合物。ZINC04259665以RdRp为靶点进行分子对接后，具有良好的对接得分。分子动力学模拟结果表明，ZINC04259665与3CLpro/RdRp结合稳定。ADME预测表明ZINC04259665具有良好的耐药性。结论:以3CLpro/RdRp为靶点，通过分子动力学模拟和ADME预测，采用分步策略筛选得分最高的化合物，发现ZINC04259665具有良好的开发潜力，可作为后续命中化合物进行研究。此外，获得的数据为抗SARS-COV-2药物的合理开发提供了相关信息。

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

Letters in Drug Design & Discovery 医学-医药化学

CiteScore

1.80

自引率

10.00%

发文量

245

审稿时长

3 months

期刊介绍： Aims & Scope Letters in Drug Design & Discovery publishes letters, mini-reviews, highlights and guest edited thematic issues in all areas of rational drug design and discovery including medicinal chemistry, in-silico drug design, combinatorial chemistry, high-throughput screening, drug targets, and structure-activity relationships. The emphasis is on publishing quality papers very rapidly by taking full advantage of latest Internet technology for both submission and review of manuscripts. The online journal is an essential reading to all pharmaceutical scientists involved in research in drug design and discovery.