The Quest for Ligands Against Kinesin Motor Protein Eg5

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 mu M, 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.