A deep learning-based theoretical protocol to identify potentially isoform-selective PI3Kα inhibitors

Phosphoinositide 3-kinase alpha (PI3Kα) is one of the most frequently dysregulated kinases known for their pivotal role in many oncogenic diseases. While the side effects linked to existing drugs against PI3Kα-induced cancers provide an avenue for further research, the significant structural conservation among PI3Ks makes it extremely difficult to develop new isoform-selective PI3Kα inhibitors. Embracing this challenge, we herein designed a hybrid protocol by integrating machine learning (ML) with in silico drug-designing strategies. A deep learning classification model was developed and trained on the physicochemical descriptors data of known PI3Kα inhibitors and used as a screening filter for a database of small molecules. This approach led us to the prediction of 662 compounds showcasing appropriate features to be considered as PI3Kα inhibitors. Subsequently, a multiphase molecular docking was applied to further characterize the predicted hits in terms of their binding affinities and binding modes in the targeted cavity of the PI3Kα. As a result, a total of 12 compounds were identified whereas the best poses highlighted the efficiency of these ligands in maintaining interactions with the crucial residues of the protein to be targeted for the inhibition of associated activity. Notably, potential activity of compound 12 in counteracting PI3Kα function was found in a previous in vitro study. Following the drug-likeness and pharmacokinetic characterizations, six compounds (compounds 1, 2, 3, 6, 7, and 11) with suitable ADME-T profiles and promising bioavailability were selected. The mechanistic studies in dynamic mode further endorsed the potential of identified hits in blocking the ATP-binding site of the receptor with higher binding affinities than the native inhibitor, alpelisib (BYL-719), particularly the compounds 1, 2, and 11. These outcomes support the reliability of the developed classification model and the devised computational strategy for identifying new isoform-selective drug candidates for PI3Kα inhibition.

In silico drug discovery; Isoform-selective inhibitors; Machine learning; Molecular dynamics simulation; Multilayer perceptron; Phosphoinositide 3-kinase alpha.