Barakat, Khaled H.; Huzil, J. Torin; Jordan, Kirk E.; Evangelinos, Constantinos; Houghton, Michael; Tuszynski, Jack
A Computational Model for Overcoming Drug Resistance Using Selective Dual-Inhibitors for Aurora Kinase A and Its T217D Variant
MOLECULAR PHARMACEUTICS, 10:4572-4589, DEC 2013

The human Aurora kinase-A (AK-A) is an essential mitotic regulator that is frequently overexpressed in several cancers. The recent development of several novel AK-A inhibitors has been driven by the well-established association of this target with cancer development and progression. However, resistance and cross-reactivity with similar kinases demands an improvement in our understanding of key molecular interactions between the Aurora kinase-A substrate binding pocket and potential inhibitors. Here, we describe the implementation of state-of-the-art virtual screening techniques to discover a novel set of Aurora kinase-A ligands that are predicted to strongly bind not only to the wild type protein, but also to the T217D mutation that exhibits resistance to existing screened ligands was shown to be more selective toward the mutant selective subsets of ligands provides a unique pharmacological tool both kinase cross-reactivity and drug resistance associated with the inhibitors. Furthermore, a subset of these computationally variant over the wild type protein. The description of these for the design of new drug regimens aimed at overcoming Aurora kinase-A T217D mutation.

DOI:10.1021/mp4003893

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