Session: Undergraduate Research Posters: Computational Chemistry:

Kinases and their signaling pathways play a biologically important role in a wide range of cellular functions and because of this they are often targets of dysregulation for oncogenesis. Thus, within the last three decades kinase inhibition has played an increasingly prominent role in cancer therapy. Currently, there are five classes of kinase inhibitors dependent upon the location of binding. Type II inhibitors are of special importance due to their high specificity and unique ability to bind to the allosteric hydrophobic pocket adjacent to the ATP binding site. In our work we use a computational approach to provide an in-depth analysis and comparison of binding affinities and allosteric interactions of type II inhibitors with multiple kinases in the CMGC family. Through docking simulations and analysis of transfer entropy patterns, we provide insight into electrostatic complementarity, transfer entropy, binding free energy, and conformational differences upon inhibitor binding. We find that the kinase P-loop domain plays an important, but different role in allosteric regulation for each kinase family member. We provide a detailed structural rationale for the specificity of different type II inhibitors and we present how different secondary structures effect transfer entropy within the CMGC family of kinases.

Megan Kelly

Appearances