Discovery of Novel c‑MET Inhibitors for Hepatocellular Carcinoma Using an Integrated Virtual Screening Approach.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-06-26 eCollection Date: 2025-07-10 DOI:10.1021/acsmedchemlett.5c00173

Rushan Fei, Na Lin, Xin Zhang, Lei Xu, Qingnan Zhang, Zhichao Pan, Xiaowu Dong, Weilin Wang

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引用次数: 0

Abstract

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide, with the efficacy of current targeted therapies limited by drug resistance and adverse effects. The receptor tyrosine kinase c-MET has been identified as a promising target for HCC therapy due to its involvement in tumor progression, metastasis, and poor prognosis. However, no c-MET inhibitors have been approved for HCC treatment. This study integrates a multistep virtual screening workflow, incorporating molecular docking, machine learning-based predictions, and molecular dynamics simulations, to identify novel c-MET inhibitors with unique structural frameworks. Among several promising candidates, compound 10 exhibited potent c-MET inhibition and selective antiproliferative effects against the HCC cell line Hep3B. Further molecular dynamics simulations confirmed the binding stability of compound 10 with c-MET, highlighting key interactions that contribute to its inhibitory activity. These findings provide valuable insights into the development of c-MET inhibitors with potential therapeutic applications for HCC.

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使用集成虚拟筛选方法发现新的肝细胞癌c - MET抑制剂。

肝细胞癌（HCC）仍然是全球癌症相关死亡的主要原因之一，目前靶向治疗的疗效受到耐药性和不良反应的限制。酪氨酸激酶c-MET受体由于参与肿瘤进展、转移和预后不良，已被确定为HCC治疗的一个有希望的靶点。然而，尚未有c-MET抑制剂被批准用于HCC治疗。该研究整合了多步虚拟筛选工作流程，结合分子对接、基于机器学习的预测和分子动力学模拟，以识别具有独特结构框架的新型c-MET抑制剂。在几种有希望的候选药物中，化合物10对HCC细胞系Hep3B表现出有效的c-MET抑制和选择性抗增殖作用。进一步的分子动力学模拟证实了化合物10与c-MET结合的稳定性，强调了促进其抑制活性的关键相互作用。这些发现为开发具有潜在HCC治疗应用价值的c-MET抑制剂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.