Monastrol disrupts KIFC1-ATP dynamics: Towards newer anticancer mechanism

Abstract

Mitotic kinesins are eukaryotic proteins that play a vital role in cellular mitosis. Their over-expression in malignant rather than normal cells and their specific cellular role made kinesin inhibitors a promising cancer therapeutics. The realization of in-vitro antitumor activity of the investigational molecule-monastrol-was traced to its allosteric inhibition of the ATPase activity of the motor domain of Human Kensin-5 (Eg5) and prompted extensive efforts towards kinesin inhibitors. Many reports pointed to the prospect of Kinesin-like protein (KIFC1) as a novel anticancer target. Nevertheless, no verified KIFC1-inhibitor crystallized structure has been reported so far, confirming the scarcity of molecular studies devoted to deciphering claimed potentiality. The significant structural resemblance across the kinesins superfamily sparked our interest in investigating monastrol as a KIFC1 inhibitor.Time-scale findings of molecular dynamics simulation and molecular mechanics/generalized-born surface area (MM/GBSA) methods revealed that monastrol binds with high affinity to an allosteric pocket, inducing notable dynamical alterations evidenced by increased structural stability, rigidity, compactness, and overall folding tendency of KIFC1. Further, these conformational events negatively impacted the affinity of ATP to its site disrupting the essential ATP-KIFC1 dynamics leading to consequential loss of functionality. We concluded that monastrol can act as non-competitive inhibitor of KIFC1 and these findings speculate new anticancer mechanism contributing to the design of highly selective and novel cancer therapeutics.