Yasir Mohammad, Patra Jeevan, Maurya Rahul K, Tripathi Alok S, Pathan Hero Khan
School of Pharmacy, ITM University, Gwalior, Madhya Pradesh.
Amity Institute of Pharmacy, Amity University, Noida, Uttar Pradesh.
Anticancer Drugs. 2025 Jun 24. doi: 10.1097/CAD.0000000000001749.
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.
谷胱甘肽过氧化物酶4（GPX4）在调节铁死亡和维持氧化还原稳态中起关键作用，使其成为耐药性癌症中的一个关键靶点。最近的研究表明，对GPX4的变构抑制可以克服耐药机制。本研究旨在使用计算方法鉴定具有潜在GPX4变构抑制作用的天然产物。对来自开放天然产物集合（COCONUT）数据库的125415种天然化合物的精选文库进行了全面的虚拟筛选。使用UCSF DOCK6针对GPX4的变构位点（PDB ID：7U4N）进行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软件包进行的100纳秒分子动力学模拟对顶级候选物进行评估。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。与共结晶配体（-3.15 kcal/mol）相比，五种天然化合物——槲皮素、玉米素核糖苷、呋喃核糖基马卡鲁维酸C、特克莱纳他林碱B和东莨菪碱——表现出更高的结合亲和力（对接分数范围为-4.01至-4.95 kcal/mol），在GPX4的关键半胱氨酸66残基处有显著相互作用。MM-PBSA分析显示出高度有利的结合自由能（高达-37.94 kcal/mol），表明配体-蛋白质复合物稳定。分子动力学模拟证实了结构稳定性，均方根偏差和均方根波动最小。ADMET分析表明具有良好的溶解性、吸收性、低毒性和良好的药物相似性。本研究突出了天然产物作为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性质，值得进一步进行体外和体内研究，以开发作为靶向耐药性癌症的抗癌药物。
