Investigation the Mechanism of Interaction between Inhibitor ALISERTIB with Protein Kinase A and B Using Modeling, Docking and Molecular Dynamics Simulation
Subject Areas : International Journal of Bio-Inorganic Hybrid Nanomaterials
Keywords: Alisertib, ATP-binding site, Glycine-rich loop, Kinase,
Abstract :
The high level of conservation in ATP-binding sites of protein kinases increasingly demandsthe quest to find selective inhibitors with little cross reactivity. Kinase kinases are a recently discoveredgroup of Kinases found to be involved in several mitotic events. These proteins represent attractivetargets for cancer therapy with several small molecule inhibitors undergoing different phase of clinicaltrials. Alisertib, a synthetic inhibitor of Kinase kinases, acts as an ATP-competitive compound whichhas been proved to be selective for Kinase A and is currently being evaluated in the phase I trial forpatients with advanced solid tumors. However, the structural details on the selectivity of Alisertib towardsKinase-A over Kinase B are still not resolved. To investigate the structural details of this selectivity, thecomplexes of Kinase A and B with Alisertib were modeled and evaluated using molecular dynamicssimulation and docking techniques. The predicted free energy for the binding of Alisertib to Kinase Aand B suggests stronger interactions between Alisertib and Kinase A. Results also indicate that thereare a strong attraction and anion- pi stacking interaction between the Phe144 in Kinase A and CLBBatom and benzazepine scaffold of Alisertib. As well as it seems a desired anion-pi stacking interactionwas created between the carboxyl group of the side chain of Asp274 and fluoro methoxyphenyl ring ofAlisertib. Furthermore, Kinase kinases contain a conserved hydrophobic ligand-binding pocket that ishighly involved in ligand binding specificity. Taken together it seems that the mentioned difference in thebinding pockets of Kinase A and B are the key factors responsible for selectivity.