Molecular Docking Investigation of Eg5 Enzyme Inhibition by Hydroxyquinolone Derivatives

Kinesin spindle protein (KSP), also known as Eg5, is a member of the kinesin superfamily of molecular motor proteins that utilize the energy generated by ATP hydrolysis to facilitate the transport and organization of microtubules and other intracellular components. KSP plays a crucial role in the formation and maintenance of the bipolar mitotic spindle and is therefore considered an attractive molecular target for anticancer drug development. Since the discovery of Monastrol in 1999, numerous KSP inhibitors have been identified and investigated. Most reported KSP inhibitors are ATP-uncompetitive allosteric inhibitors that reversibly inhibit the ATPase activity of Eg5 and encompass a wide range of structural classes. In the present study, hydroxyquinolone derivatives, which are known for their broad range of pharmacological activities, including anticancer, and anti-inflammatory properties, were investigated as potential Eg5 inhibitors. Molecular docking studies were performed to evaluate the binding modes and predicted affinities of the investigated derivatives toward the Eg5 binding site. All compounds exhibited favorable docking scores ranging from −6.92 to −7.02 kcal/mol, indicating their potential to establish stable interactions with the enzyme. The most favorably ranked derivatives were accommodated within the active binding pocket through hydrogen bonding, hydrophobic contacts, and other stabilizing interactions. In particular, the hydroxyl groups present in the hydroxyquinolone scaffold appeared to contribute to ligand recognition and binding stabilization through hydrogen bonding interactions with key amino acid residues.