Molecular Dynamics Simulations to Investigate the Binding Mode of the Natural Product Liphagal with Phosphoinositide 3-Kinase [alpha]

Abstract

Phosphatidylinositol 3-kinase [alpha] (PI3K[alpha]) 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 PI3K[alpha] inhibitor. Molecular docking and molecular dynamics simulations were performed to explore the dynamic behaviors of PI3K[alpha] 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 PI3K[alpha]. Thus, a new strategy for the rational design of more potent analogs of liphagal against PI3K[alpha] is provided. Our proposed PI3K[alpha]/liphagal binding mode would be beneficial for the discovery of new active analogs of liphagal against PI3K[alpha].