{"title":"Computational discovery of novel GPX4 inhibitors from herbal sources as potential ferroptosis inducers in cancer therapy","authors":"Mohammad Mahdi Mokhtari Tabar , Abdolmajid Ghasemian , Amin Kouhpayeh , Esmaeil Behmard","doi":"10.1016/j.abb.2024.110231","DOIUrl":null,"url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110231"},"PeriodicalIF":3.8000,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Archives of biochemistry and biophysics","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0003986124003539","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
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.