Rational design and preliminary validation of phosphoinositide-3-kinase (PI3K) modulators

Abstract

Phosphoinositide-3-kinases (PI3K) form part of a pathway that becomes activated in cancer such as spinal chordomas. Therefore, this pathway is both a challenge and an opportunity for the therapeutic intervention in cancer. The two approaches used in this study include virtual screening and de novo design to computationally dock the novel antagonist small molecule into the PI3K ligand binding pocket and determine its optimally bound conformation. PDB crystallographic deposition 5ITD, described the bound co-ordinates of the PI3Kδ receptor bound to the small molecular inhibitor 5-{4-[3-(4-acetylpiperazine-1-carbonyl)phenyl]quinazolin-6-yl}-2-methoxypyridine-3-carbonitrile and PDB 6C1S, described the bound co-ordinates of the PI3Kу receptor bound to the pyrrolopyridinone inhibitor {4-[2-(5,6-dimethoxypyridin-3-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4- b]pyridin-6-yl]-1H-pyrazol-1-yl}acetonitrile were selected for this study. An apo-PI3K receptor was consequently generated through molecular simplification using SYBYL®-X. Its scaffold was used to create a pharmacophore for use in a virtual screening exercise using the online database ZINCPharmer®. The resulting hits were screened for Lipinski Rule compliance and docked into the modelled protomol. These were then ranked in order of affinity. For de novo design, three seed structures were modelled based on the 2D topology map. These structures included all the structural moieties which were essential for binding. After using the growing process in LigBuilder®, the structures obtained were filtered according to Lipinski’s Rule of five and were then divided according to family and affinity. 52 Lipinski Rule Compliant molecules were identified through de novo and virtual screening. The structures that had the highest affinity for the target ligand binding pocket are recommended for further validation.