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- Title
Molecular Dynamics Simulations to Investigate the Binding Mode of the Natural Product Liphagal with Phosphoinositide 3-Kinase α.
- Authors
Yanjuan Gao; Ying Ma; Guangde Yang; Yiping Li
- 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.
- Subjects
PHOSPHOINOSITIDES; ANTINEOPLASTIC agent development; MOLECULAR docking; VAN der Waals forces; DRUG design
- Publication
Molecules, 2016, Vol 21, Issue 7, p857
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules21070857