In Silico Screening for Chemical Scaffolds as Suitable Natural Inhibitors of Kinesin EG5 Divulges Morelloflavone, a Biflavonoid, as Potential Anticancer Compound

Abstract

Natural products remain a source of chemical scaffold pool for drug design and development. Kinesin Eg5 has emerged as a clinical target for anticancer agents. In our search for potent natural inhibitors of kinesin Eg5, we employed in silico tools to screen selected diverse chemical scaffolds (compounds) that were obtained from medicinal plants. Surprisingly, the molecular interaction analysis for the selected compounds adjudged morelloflavone (a biflavonoid) as a potential ATP-noncompetitive inhibitor of kinesin Eg5 protein which occupied the putative L5/α2/α3 allosteric pocket on the protein. Compared to STLC with binding energy value −10.0 Kcal/mol, morelloflavone displayed binding energy value of −10.2 Kcal/mol and a 90 percent binding site similarity. It is also worth noting that morelloflavone was embedded within the cavity formed by amino acid residues Ile-136, Glu-116, Glu-118, Trp-127, Gly-117, Ala-133, Glu-215, Leu-214, Tyr-211 and hence, displayed a reliable tendency to block the enzymatic catalysis of kinesin Eg5 allosterically. The compound established hydrogen bonds with Glu-118 and Tyr-211 having minimum length of 2.97‎A and hydrophobic interactions occurred with alkyl side chain of residues Gly-117, Glu-116, Ala-218, Ile-136, Arg-119 and Asp-130 while π-stacking interaction is observed between the aromatic ring of morelloflavone and Arg-119. These interactions anchored morelloflavone into the binding site. The results obtained in this work indicate the strong affinity and inhibitory potential of this compound on kinesin Eg5, hence lending credence to the yet untapped anticancer capacities of morelloflavone. We therefore suggest in vitro and ex vivo evaluation of this compound as anticancer agent targeting kinesin Eg5 protein.