Maryam Eskordi - Biophysics and Computational Biology Laboratory, Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran
Navid Mogharrab - Biophysics and Computational Biology Laboratory, Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran- Biophysics and Computational Biology Laboratory, Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran
Fatemeh Yadegari - Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran

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 mentioned2difference in the binding pockets of Kinase A and B are the key factors responsible forselectivity.

Kinase, Alisertib, ATP-binding site, Glycine-rich loop