Design, Synthesis, Evaluation, and Molecular Dynamics Simulation of SARS-CoV-2 M^pro Inhibitors.

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-03-17 eCollection Date: 2025-04-10 DOI:10.1021/acsmedchemlett.5c00065

Qinghua Yang, Keli Zong, Xu Zhao, Fenghua Zhang, Fei Li, Xingzhou Li

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引用次数: 0

Abstract

COVID-19, caused by SARS-CoV-2, is a highly contagious disease with significant transmissibility and pathogenicity. The main protease of SARS-CoV-2 (M^pro or 3CL^pro) is crucial for viral replication, making it a key therapeutic target. Nirmatrelvir, a promising M^pro inhibitor, contains a trifluoroacetyl group in its P4 fragment, which presents opportunities for further optimization. This study aims to enhance the inhibitory activity of nirmatrelvir through structural modification of the P4 fragment. Using a computer-aided drug design (CADD) approach, 11 novel compounds were identified based on molecular docking scores, binding free energy, predicted ADMET properties, structural diversity, synthetic feasibility, and inhibitory activity. IC₅₀ measurements and molecular dynamics (MD) simulations demonstrated significant inhibitory potential for most compounds, with IC₅₀ values ranging from 0.0435-0.9989 μM. Notably, compounds 2-5a and 2-5f exhibited inhibitory activity against SARS-CoV-2 M^pro comparable to that of nirmatrelvir. These findings offer valuable insights for the development of anti-SARS-CoV-2 therapeutics.

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SARS-CoV-2 Mpro抑制剂的设计、合成、评价及分子动力学模拟

COVID-19是由SARS-CoV-2引起的高传染性疾病，具有显著的传播力和致病性。SARS-CoV-2的主要蛋白酶（Mpro或3CLpro）对病毒复制至关重要，使其成为关键的治疗靶点。Nirmatrelvir是一种很有前景的Mpro抑制剂，其P4片段中含有三氟乙酰基，这为进一步优化提供了机会。本研究旨在通过对P4片段进行结构修饰来增强nirmatrelvir的抑制活性。利用计算机辅助药物设计（CADD）方法，基于分子对接分数、结合自由能、预测ADMET性质、结构多样性、合成可行性和抑制活性鉴定了11个新化合物。IC50测试和分子动力学（MD）模拟表明，大多数化合物具有显著的抑制潜力，IC50值在0.0435 ~ 0.9989 μM之间。值得注意的是，化合物2-5a和2-5f对SARS-CoV-2 Mpro的抑制活性与nirmatrelvir相当。这些发现为开发抗sars - cov -2疗法提供了有价值的见解。

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

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.