Exploring natural products for allosteric inhibition of glutathione peroxidase 4 in drug-resistant cancers via molecular docking and dynamics.

IF 2.2 4区 医学 Q3 ONCOLOGY
Anti-Cancer Drugs Pub Date : 2025-10-01 Epub Date: 2025-06-24 DOI:10.1097/CAD.0000000000001749
Mohammad Yasir, Jeevan Patra, Rahul K Maurya, Alok S Tripathi, Hero Khan Pathan
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引用次数: 0

Abstract

Glutathione peroxidase 4 (GPX4) plays a pivotal role in regulating ferroptosis and maintaining redox homeostasis, making it a critical target in drug-resistant cancers. Recent studies suggest that allosteric inhibition of GPX4 could overcome resistance mechanisms. This study aimed to identify natural products with potential allosteric inhibition of GPX4 using computational approaches. A comprehensive virtual screening was conducted on a curated library of 125 415 natural compounds derived from the COlleCtion of Open Natural ProdUcTs (COCONUT) database. Structure-based virtual screening and molecular docking were performed against the allosteric site of GPX4 (PDB ID: 7U4N) using UCSF DOCK6. The top candidates were evaluated through binding free energy calculations [molecular mechanics Poisson-Boltzmann surface area (MM-PBSA)] and 100 ns molecular dynamics simulations using the AMBER20 package. Pharmacokinetic and toxicity profiles were assessed through absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis. Five natural compounds - quercetin, zeatinriboside, ribofuranosylmakaluvic acid C, tecleanatalensine B, and scopolamine - exhibited superior binding affinities (docking scores ranging from -4.01 to -4.95 kcal/mol) compared with the cocrystallized ligand (-3.15 kcal/mol), with significant interactions at the key Cys66 residue of GPX4. MM-PBSA analysis revealed highly favorable binding free energies (up to -37.94 kcal/mol), indicating stable ligand-protein complexes. Molecular dynamic simulations confirmed structural stability, with minimal root mean square deviation and root mean square fluctuations. ADMET profiling suggested favorable solubility, absorption, low toxicity, and good drug-likeness. This study highlights the potential of natural products as allosteric inhibitors of GPX4. The identified compounds demonstrated strong and stable interactions with the GPX4 allosteric site and possessed desirable pharmacokinetic properties, warranting further in-vitro and in-vivo investigations for potential development as anticancer agents targeting drug-resistant cancers.

通过分子对接和动力学探索耐药癌症谷胱甘肽过氧化物酶4变构抑制的天然产物。
谷胱甘肽过氧化物酶4 (Glutathione peroxidase 4, GPX4)在调节铁凋亡和维持氧化还原稳态中起关键作用,是耐药癌症的重要靶点。最近的研究表明,GPX4的变构抑制可以克服耐药机制。本研究旨在利用计算方法鉴定具有GPX4潜在变构抑制作用的天然产物。对来自Open natural ProdUcTs (COCONUT)数据库的124515种天然化合物进行了全面的虚拟筛选。利用UCSF DOCK6对GPX4 (PDB ID: 7U4N)的变构位点进行了基于结构的虚拟筛选和分子对接。通过结合自由能计算[分子力学泊松-玻尔兹曼表面积(MM-PBSA)]和使用AMBER20包进行100 ns分子动力学模拟来评估最佳候选者。通过吸收、分布、代谢、排泄和毒性(ADMET)分析评估药代动力学和毒性概况。5种天然化合物槲皮素、玉米苷、核呋喃基马柳酸C、tecleanatalenine B和东莨菪碱的结合亲和力(对接分数为-4.01 ~ -4.95 kcal/mol)优于共晶配体(对接分数为-3.15 kcal/mol),在GPX4的关键Cys66残基上具有显著的相互作用。MM-PBSA分析显示了良好的结合自由能(高达-37.94 kcal/mol),表明配体-蛋白复合物稳定。分子动力学模拟证实了结构稳定性,具有最小的均方根偏差和均方根波动。ADMET分析表明其具有良好的溶解性、吸收性、低毒性和良好的药物相似性。这项研究强调了天然产物作为GPX4变构抑制剂的潜力。所鉴定的化合物与GPX4变构位点表现出强而稳定的相互作用,并具有理想的药代动力学特性,因此需要进一步的体外和体内研究,以开发针对耐药癌症的抗癌药物。
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
Anti-Cancer Drugs
Anti-Cancer Drugs 医学-药学
CiteScore
3.80
自引率
0.00%
发文量
244
审稿时长
3 months
期刊介绍: Anti-Cancer Drugs reports both clinical and experimental results related to anti-cancer drugs, and welcomes contributions on anti-cancer drug design, drug delivery, pharmacology, hormonal and biological modalities and chemotherapy evaluation. An internationally refereed journal devoted to the fast publication of innovative investigations on therapeutic agents against cancer, Anti-Cancer Drugs aims to stimulate and report research on both toxic and non-toxic anti-cancer agents. Consequently, the scope on the journal will cover both conventional cytotoxic chemotherapy and hormonal or biological response modalities such as interleukins and immunotherapy. Submitted articles undergo a preliminary review by the editor. Some articles may be returned to authors without further consideration. Those being considered for publication will undergo further assessment and peer-review by the editors and those invited to do so from a reviewer pool.
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