From IPI-549 to Novel Compounds: A Novel Strategy Integrating 3D-QSAR, Scaffold Growth, Molecular Docking, and...

Phosphoinositide-3-kinase gamma (PI3Kγ) has emerged as a valuable therapeutic target for various diseases. However, there is a notable scarcity of inhibitors that have advanced to clinical studies, highlighting the urgent need for the development of novel PI3Kγ inhibitors.

A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was conducted to investigate the structure-activity relationships of PI3Kγ inhibitors. A scaffold growth strategy was employed to design novel compounds. Furthermore, a virtual screening workflow integrating drug-likeness filtering, 3D-QSAR predictions, and molecular docking was established.

An optimal CoMFA model was developed with q² = 0.752, r² = 0.995, and r²pred = 0.736, revealing key structural features and interactions crucial for selective PI3Kγ inhibition. Using the N-phenyl isoquinolinone core of IPI-549 as a template, new compounds were generated via a reaction-based scaffold growth approach. Following drug-likeness evaluation, 3DQSAR predictions, and molecular docking, nine compounds demonstrated superior predicted activity compared to IPI-549. Three top-ranked hits were subsequently subjected to molecular dynamics simulations and binding free energy calculations, providing insights into the PI3Kγ/Hit binding mechanism and identifying critical residues governing selectivity, including MET804, TRP812, ILE831, VAL882, and MET953.

Developing selective PI3Kγ inhibitors is challenging due to the high homology among kinase structures. IPI-549, the first PI3Kγ inhibitor to enter clinical trials, served as a suitable template for designing novel selective inhibitors. This study applied computer-aided drug design strategies to formulate promising new PI3Kγ inhibitors.

The present workflow provides an effective and precise approach for identifying novel PI3Kγ inhibitors and offers valuable guidance for the rational design of selective PI3Kγ- targeted therapeutics.