Ahmet Fatih Sahin, Simone Carradori, Alessia Ricci, Muhammad Rashad, Atilla Akdemir
{"title":"The Quest for Ligands Against Kinesin Motor Protein Eg5","authors":"Ahmet Fatih Sahin, Simone Carradori, Alessia Ricci, Muhammad Rashad, Atilla Akdemir","doi":"10.1002/ardp.70010","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>The Kinesin Eg5 motor protein is essential for the formation of the mitotic spindles and chromosome segregation, which is necessary for cell division. The inhibition of Eg5 has emerged as a potential therapeutic strategy for inhibiting the uncontrolled proliferation of cancer cells. This study aims to identify inhibitors targeting the allosteric site I of Eg5. To this end, a hierarchical virtual screening was applied to screen the ZINC20-Anodyne compound library comprising approximately 11 million druglike compounds. The procedure includes a shape similarity screening, a pharmacophore screening, docking studies with subsequent re-scorings, molecular dynamics simulations, and Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) binding free energy calculations and resulted in the selection of four compounds for Eg5 inhibition assays. One compound displays an IC<sub>50</sub> value of 29 µM, while the remaining three compounds show weaker inhibition of Kinesin Eg5. As such, structurally novel Kinesin Eg5 inhibitors have been obtained for further hit-to-lead optimization programs.</p>\n </div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 5","pages":""},"PeriodicalIF":4.3000,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Archiv der Pharmazie","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ardp.70010","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
The Kinesin Eg5 motor protein is essential for the formation of the mitotic spindles and chromosome segregation, which is necessary for cell division. The inhibition of Eg5 has emerged as a potential therapeutic strategy for inhibiting the uncontrolled proliferation of cancer cells. This study aims to identify inhibitors targeting the allosteric site I of Eg5. To this end, a hierarchical virtual screening was applied to screen the ZINC20-Anodyne compound library comprising approximately 11 million druglike compounds. The procedure includes a shape similarity screening, a pharmacophore screening, docking studies with subsequent re-scorings, molecular dynamics simulations, and Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) binding free energy calculations and resulted in the selection of four compounds for Eg5 inhibition assays. One compound displays an IC50 value of 29 µM, while the remaining three compounds show weaker inhibition of Kinesin Eg5. As such, structurally novel Kinesin Eg5 inhibitors have been obtained for further hit-to-lead optimization programs.
期刊介绍:
Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.