title: Molecular Dynamics Simulations to Investigate the Binding Mode of the Natural Product Liphagal with Phosphoinositide 3-Kinase α.
abstract: Phosphatidylinositol 3-kinase α (PI3Kα) is an attractive target for anticancer drug design. Liphagal, isolated from the marine sponge Aka coralliphaga, possesses the special "liphagane" meroterpenoid carbon skeleton and has been demonstrated as a PI3Kα inhibitor. Molecular docking and molecular dynamics simulations were performed to explore the dynamic behaviors of PI3Kα binding with liphagal, and free energy calculations and energy decomposition analysis were carried out by use of molecular mechanics/Poisson-Boltzmann (generalized Born) surface area (MM/PB(GB)SA) methods. The results reveal that the heteroatom rich aromatic D-ring of liphagal extends towards the polar region of the binding site, and the D-ring 15-hydroxyl and 16-hydroxyl form three hydrogen bonds with Asp810 and Tyr836. The cyclohexyl A-ring projects up into the upper pocket of the lipophilic region, and the hydrophobic/van der Waals interactions with the residues Met772, Trp780, Ile800, Ile848, Val850, Met922, Phe930, Ile932 could be the key interactions for the affinity of liphagal to PI3Kα. Thus, a new strategy for the rational design of more potent analogs of liphagal against PI3Kα is provided. Our proposed PI3Kα/liphagal binding mode would be beneficial for the discovery of new active analogs of liphagal against PI3Kα.
authors.affiliation: School of Pharmacy, Xi'an Jiaotong University, No. 76 Yanta West Road, Xi'an 710061, China. gaoyanjuan@stu.xjtu.edu.cn.
authors.forename: Yanjuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: School of Pharmacy, Xi'an Jiaotong University, No. 76 Yanta West Road, Xi'an 710061, China. my417815@stu.xjtu.edu.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.affiliation: School of Pharmacy, Xi'an Jiaotong University, No. 76 Yanta West Road, Xi'an 710061, China. jmw52@mail.xjtu.edu.cn.
authors.forename: Guangde
authors.initials: G
authors.lastname: Yang
authors.affiliation: School of Pharmacy, Xi'an Jiaotong University, No. 76 Yanta West Road, Xi'an 710061, China. yipingli@mail.xjtu.edu.cn.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Li
mesh_terms: D001665:Binding Sites; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D013729:Terpenes / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D001688:Biological Products; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013729:Terpenes; C513880:liphagal
keywords: anti-tumor; binding mode; liphagal; molecular dynamics simulation; phosphatidylinositol 3-kinase α