Polyphenol MHQP as an allosteric inhibitor of Kinesin-5: Cease the molecular catwalk of “Drunken Sailor”

Abstract

Human Kinesin-5 (KIF-11/Eg5), a major anticancer drug target, is a plus end-directed motor protein that is involved in spindle dynamics and principally involved in mitosis. In the present study, a computer-aided rational drug discovery approach has been applied to search for potential allosteric inhibitors against Eg5. Accordingly, virtual screening of naturally occurring secondary metabolites and their commercially available synthetic derivatives indicates 2-(9b- methyl-2,3,3a,4,5,9b-hexahydrofuro [3,2 c] quinolin-4-yl) phenol (MHQP), a hexahydrofuro [3,2-c] quinolone derivative as a potential therapeutic lead molecule against Eg5. The present study provides a structural glimpse of MHQP binding at the monastrol binding site of Eg5 with a vivid description of its plausible mode of Eg5 inhibition. Moreover, the in silico data also supports the superiority of MHQP over the well-characterized Eg5 inhibitor Arry-520 in terms of augmented binding affinity as well as to cope with Arry-520 resistant mutants of Eg5. Structure-guided mechanistic details of MHQP-induced inhibition of Eg5 and its predicted pharmacodynamics properties have been presented herein.