Investigation the Mechanism of Interaction between Inhibitor ALISERTIB with Protein Kinase A and B Using Modeling, Docking and Molecular Dynamics Simulation

Document Type : Research Paper


The high level of conservation in ATP-binding sites of protein kinases increasingly demands
the quest to find selective inhibitors with little cross reactivity. Kinase kinases are a recently discovered
group of Kinases found to be involved in several mitotic events. These proteins represent attractive
targets for cancer therapy with several small molecule inhibitors undergoing different phase of clinical
trials. Alisertib, a synthetic inhibitor of Kinase kinases, acts as an ATP-competitive compound which
has been proved to be selective for Kinase A and is currently being evaluated in the phase I trial for
patients with advanced solid tumors. However, the structural details on the selectivity of Alisertib towards
Kinase-A over Kinase B are still not resolved. To investigate the structural details of this selectivity, the
complexes of Kinase A and B with Alisertib were modeled and evaluated using molecular dynamics
simulation and docking techniques. The predicted free energy for the binding of Alisertib to Kinase A
and B suggests stronger interactions between Alisertib and Kinase A. Results also indicate that there
are a strong attraction and anion- pi stacking interaction between the Phe144 in Kinase A and CLBB
atom and benzazepine scaffold of Alisertib. As well as it seems a desired anion-pi stacking interaction
was created between the carboxyl group of the side chain of Asp274 and fluoro methoxyphenyl ring of
Alisertib. Furthermore, Kinase kinases contain a conserved hydrophobic ligand-binding pocket that is
highly involved in ligand binding specificity. Taken together it seems that the mentioned difference in the
binding pockets of Kinase A and B are the key factors responsible for selectivity.