title: Characterization of molecular recognition of phosphoinositide-3-kinase α inhibitor through molecular dynamics simulation.
abstract: Phosphatidylinositol 3-kinase α (PI3Kα) is a promising target for anticancer drug discovery due to its overactivation in tumor cells. To systematically investigate the interactions between PI3Kα and PIK75 which is the most selective PI3Kα inhibitor reported to date, molecular docking, molecular dynamics simulation, and ensuing energetic analysis were utilized. The binding free energy between PI3Kα and PIK75 is -10.04 kcal•mol(-1) using MMPBSA method, while -13.88 kcal•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 PI3Kα is predicted. The conserved hydrophobic adenine region of PI3Kα 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 PI3Kα presented in this study may help design high affinity and selective compounds to target PI3Kα.
authors.affiliation: Department of Pharmacy, College of Medicine, Xi'an Jiaotong University, Xi'an, Peoples Republic of China.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Li
authors.forename: Jiye
authors.initials: J
authors.lastname: Zhang
authors.forename: Delong
authors.initials: D
authors.lastname: He
authors.forename: Qi
authors.initials: Q
authors.lastname: Liang
authors.forename: Yawen
authors.initials: Y
authors.lastname: Wang
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D006835:Hydrazones / Q000737:chemistry*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007527:Isoenzymes; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D011789:Quantum Theory; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity; D013449:Sulfonamides / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006835:Hydrazones; D007527:Isoenzymes; C549211:PIK 75; D013449:Sulfonamides; D019870:1-Phosphatidylinositol 4-Kinase