Abstract
Kinesin spindle protein (Eg5) has been widely studied, as an important target for developing chemotherapy drugs, due to its essential role in mitotic spindle formation in mitosis. In this study, we target a promising novel allosteric site involving α4 and α6 helices, which is located 15Å from the allosteric ispinesib site. An extensive 3D-Pharmacophore structure based virtual screening was conducted. Molecular docking was carried out to explore a library of commercial molecules. Eleven compounds were identified with diversity in their chemical scaffold. Biological evaluation and MT ATPase assays revealed that compound 11 with scaffold N-(2- (2, 6 -dimethylphenoxy) phenyl) -3, 4-dihydro -3-oxo -2H-benzo[b] [1,4]oxazine-6-carboxamide inhibits Eg5 activity at (IC50=1.37±0.15µM). The chemical structure of compound 11 was confirmed by 1H-NMR and mass spectral data. The stability of compound 11 within the Eg5-ADP/ATP complex was investigated using molecular dynamic simulation technique. The free binding energy was calculated using MM/PBSA.
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