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.
Highlights
The phosphoinositide 3-kinases (PI3Ks) are attractive targets for the design of small molecule inhibitors because of the frequent occurrence of aberrant signaling of this pathway in several different disease states such as tumor, inflammatory and autoimmune diseases [1,2]
One hundred docked conformations of liphagal for Phosphatidylinositol 3-kinase α (PI3Kα) obtained in our molecular docking experiment were clustered to 5 clusters using a tolerance of 2.0 Å rmsd
Pose-B are very different, the heteroatom rich aromatic D-ring of pose-A extends towards the polar region of the binding site in PI3Kα, while the D-ring of pose-B extends towards the hinge region
Summary
The phosphoinositide 3-kinases (PI3Ks) are attractive targets for the design of small molecule inhibitors because of the frequent occurrence of aberrant signaling of this pathway in several different disease states such as tumor, inflammatory and autoimmune diseases [1,2]. The PI3Kα isoform was found to be over-activated by mutation or loss of expression of the pathway suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in colon, gastric, and breast carcinomas [6] and is likely to be the most commonly mutated kinase in the human genome [4]. As shown, is a tetracyclic meroterpenoid natural product isolated by Andersen et al in 2006 during a program designed to discover new inhibitors of PI3K signaling pathway [8]. Promising activity, bioassay-guided fractionation of the extract identified liphagal as the active component [8].
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