Class I Phospho-inositide-3-kinases (PI3Ks) Isoform-Specific Inhibition Study by the Combination of Docking and Molecular Dynamics Simulation

The combination of docking and molecular dynamics simulation is used to explain the isoform-specific selectivity between PI3Kalpha and PI3Kgamma, which are two lipid kinases in the class I PI3Ks. The protein flexibility is incorporated in docking the ligands to the ensemble of representative structures extracted from a clustering analysis of the molecular dynamics simulation in explicit aqueous solution. The reported most potent PI3Kalpha inhibitor PIK-75 was studied, and we predicted three possible PIK-75-bound conformations for PI3Kalpha and two for PI3Kgamma. Comparative analysis between the PI3Kalpha and PI3Kgamma docking experiments indicates that the residue Trp780 and Asn782 in PI3Kalpha and the corresponding residues Trp812 and Glu814 in PI3Kgamma in the solvent-accessible region can confer the PI3Kalpha and PI3Kgamma isoform specificity. The predicted bound conformations are further studied in aqueous solution by molecular dynamics simulation. The work provides a possible effective pharmacophore model for PI3Kalpha inhibitor. The dynamic behaviors of the LY294002-bound PI3Ks are studied too.