Computational discovery of novel GPX4 inhibitors from herbal sources as potential ferroptosis inducers in cancer therapy

IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Mohammad Mahdi Mokhtari Tabar , Abdolmajid Ghasemian , Amin Kouhpayeh , Esmaeil Behmard
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Abstract

Ferroptosis, a cell death regulation process dependent on iron levels, represents a promising therapeutic target in cancer treatment. However, the scarcity of potent ferroptosis inducers hinders advancement in this area. This study addresses this gap by screening the PubChem database for compounds with favorable ADMET properties to identify potential GPX4 inhibitors. A structure-based virtual screening was conducted to compare binding affinities of selected compounds to that of RSL3. The candidates—isochondrodendrine, hinokiflavone, irinotecan, and ginkgetin—were further analyzed through molecular dynamics (MD) simulations to assess their stability within the GPX4-ligand complexes. The computed binding free energies for RSL3, isochondrodendrine, hinokiflavone, irinotecan and ginkgetin were −80.12, −107.31, −132.03, and −137.52 and −91.11 kJ/mol, respectively, indicating their significantly higher inhibitory effects compared to RSL3. These findings highlight the potential for developing novel GPX4 inhibitors to promote ferroptosis, warranting further experimental validation.

Abstract Image

通过计算从草本植物中发现新型 GPX4 抑制剂,作为潜在的铁氧化诱导剂用于癌症治疗。
铁变态反应是一种依赖于铁水平的细胞死亡调节过程,是癌症治疗中一个很有前景的治疗靶点。然而,强效铁变态反应诱导剂的缺乏阻碍了这一领域的研究进展。本研究通过在 PubChem 数据库中筛选具有良好 ADMET 特性的化合物来确定潜在的 GPX4 抑制剂,从而填补了这一空白。研究人员进行了基于结构的虚拟筛选,以比较所选化合物与 RSL3 的结合亲和力。通过分子动力学(MD)模拟进一步分析了候选化合物--异软骨素、桧黄酮、伊立替康和银杏黄酮,以评估它们在 GPX4 配体复合物中的稳定性。计算得出的 RSL3、异软骨素、桧黄酮、伊立替康和银杏黄酮的结合自由能分别为 -80.12、-107.31、-132.03、-137.52 和 -91.11 kJ/mol,表明它们的抑制作用明显高于 RSL3。这些发现凸显了开发新型 GPX4 抑制剂以促进铁变态反应的潜力,值得进一步的实验验证。
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
Archives of biochemistry and biophysics
Archives of biochemistry and biophysics 生物-生化与分子生物学
CiteScore
7.40
自引率
0.00%
发文量
245
审稿时长
26 days
期刊介绍: Archives of Biochemistry and Biophysics publishes quality original articles and reviews in the developing areas of biochemistry and biophysics. Research Areas Include: • Enzyme and protein structure, function, regulation. Folding, turnover, and post-translational processing • Biological oxidations, free radical reactions, redox signaling, oxygenases, P450 reactions • Signal transduction, receptors, membrane transport, intracellular signals. Cellular and integrated metabolism.
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