Characterization of molecular recognition of Phosphoinositide-3-kinase alpha inhibitor through molecular dynamics simulation
Phosphatidylinositol 3-kinase alpha (PI3K alpha) is a promising target for anticancer drug discovery due to its overactivation in tumor cells. To systematically investigate the interactions between PI3K alpha and PIK75 which is the most selective PI3K alpha inhibitor reported to date, molecular docking, molecular dynamics simulation, and ensuing energetic analysis were utilized. The binding free energy between PI3K alpha and PIK75 is -10.04 kcalaEuro cent mol(-1) using MMPBSA method, while -13.88 kcalaEuro cent mol(-1) using MMGBSA method, which is beneficial for the binding. The van der Waals/hydrophobic and electrostatic interactions play critical roles for the binding. The binding mode of PIK75 for PI3K alpha is predicted. The conserved hydrophobic adenine region of PI3K alpha made up of Ile800, Ile848, Val850, Val851, Met922, Phe930, and Ile932 accommodates the flat 6-bromine imidazo[1,2-a]pyridine ring of PIK75. The 2-methyl-5-nitrophenyl group of PIK75 extends to the P-loop region, and has four hydrogen-bond arms with the backbone and side chain of Ser773 and Ser774. And the distinct conformation of the P-loop induced by PIK75 is speculated to be responsible for the selectivity profile of PIK75. The predicted binding mode of PIK75 for PI3K alpha presented in this study may help design high affinity and selective compounds to target PI3K alpha.
molecular dynamics simulation phosphatidylinositol 3-kinase alpha