Phosphoinositide 3-kinases (PI3Ks) are a relevant drug target because of their involvement with disease states such as cancer and diabetes. They also pose a challenge to drug development because they exist in four different isoforms (α, β, γ, and δ), which are not all involved in cancerous pathways, and should thus be targeted by isoform-selective inhibitors. This project aimed to test the ability of HADDOCK, a computational docking tool, to replicate ligand-protein interactions between isoform-selective ligands and PI3K isoforms. In order to determine which PDB conformations of PI3Kα yield reliable scores in blind docking situations, 64 dockings were performed and analyzed; eight different PI3Kα conformations were re-docked to their native ligand, as well as to the ligands of all other α conformations. A comparison of HADDOCK score and interface RMSD to the native crystal structure was performed for each docked complex. Analysis will be presented about which α structures should be utilized for blind dockings against compounds with known affinity for PI3Kγ, and the results of native γ ligands docked to PI3kα conformations.

Isoform-selective docking with HADDOCK: Assessing the effects of protein conformation and score reliability using PI3Kα

255th National Meeting (2018)

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