Structural insights into the origin of phosphoinositide 3-kinase inhibition

Class I phosphoinositide 3-kinases (PI3Ks) are currently considered as significant targets for the development of novel pharmaceuticals to treat cancers and inflammatory diseases. Since the subfamilies are differently involved in related disorders and within different subcellular compartments, the development of specific subfamily-selective inhibitors seems pertinent. However, discovery of compounds with capability to block a specific isoform of PI3K still remains as a major challenge. Therefore, herein, a combination of proteochemometric (PCM) modeling and molecular docking simulation was applied to investigate the chemical interaction space governed by α and β isoforms of PI3K and their inhibitors. Since achieving selectivity can be facilitated by considering the information of both ligand and receptor, the interaction space and selectivity of different chemical compounds towards different PI3K isoforms were explored via PCM modeling. Several approaches were applied to validate the predictivity and the robustness of the constructed model. Excellent values of 0.95, 0.85, and 0.77 were observed for the goodness of fit (R2), internal cross-validation (Q2), and external validation (Qext2), respectively. The practical application of this information was revealed via the design of a few novel compounds whereby structural modifications to the compound can exert influences on the selectivity against PI3Kα and PI3Kβ. Applying molecular docking approach, binding energies and molecular interactions were investigated for the novel compounds against both PI3Kα and PI3Kβ. Molecular docking analysis of novel design compounds was highly compatible with the PCM-based predicted biological activities. These results show that our model provided knowledge on the structural features of compounds which is promising for the design of new selective inhibitors.