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 PI3Kα and PI3Ky, 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 PI3Kα inhibitor PIK-75 was studied, and we predicted three possible PIK-75-bound conformations for PI3Kα and two for PI3Kγ. Comparative analysis between the PI3Kα and PI3Kγ docking experiments indicates that the residue Trp780 and Asn782 in PI3Kα and the corresponding residues Trp812 and Glu814 in PI3Kγ in the solvent-accessible region can confer the PI3Kα and PI3Kγ 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 PI3Kα inhibitor. The dynamic behaviors of the LY294002-bound PI3Ks are studied too.