Identification of novel scaffolds to inhibit human mitotic kinesin Eg5 targeting the second allosteric binding site using in silico methods

Abstract

Human mitotic kinesins are potential anticancer drug targets because of their essential role in mitotic cell division. The kinesin Eg5 (Kinesin-5, kif11) has gained much attention in this regard and has many inhibitors in different phases of clinical trials. All drug candidates considered for Eg5 so far binds to the binding site (Site 1) formed by the loop L5, helices α2 and α3 and are uncompetitive to ATP/ADP. Recently, it has been reported that Eg5 also has a second binding site (Site 2) formed by helices α4 and α6. In the current work, we have screened the compounds in the diversity set-III from National Cancer Institute (NCI) and Zinc database to identify potential inhibitors for Eg5 that specifically binds to the site 2. The compounds were ranked based on the glide extra precision docking scores and the top ranked compounds were found to have pyridazine scaffold. The top five compounds were further evaluated for other drug like properties. Stability of protein-ligand complexes were analyzed using molecular dynamic simulations. Our studies suggest that pyridazine analogs have good MDCK, permeability properties and high binding affinity to the human Eg5.