PI3Ka is one of the most frequently mutated proteins in human cancers. The most common mutant is the His1047Arg. Understanding how the p110a H1047R mutation causes tumorigenesis is central to developing new therapeutics for cancer. To this end, Molecular Dynamics (MD) simulations in aqueous solution were carried out for 50 ns for both the wild type and mutant proteins. Mean square fluctuation, hydrogen bond, and salt bridge analysis, were then utilized to identify regions with different levels of mobility in the two variants. Moreover, predominant conformations of the kinase domain were produced through cluster analysis. Binding site analysis of the predominant conformations in the kinase domain identified cavities in the vicinity of the H1047R mutation and the membrane binding regions. Virtual screening at these sites facilitated the discovery of novel, mutant-specific PI3Ka inhibitors that exploit the altered conformation of the mutant with respect to the wild type protein.

MD simulations of the PI3Kα wild type and mutant forms: Implications for drug design

243rd National Meeting (2012)

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