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A Computational Framework for the Design and Development of Isoform Selective PI3Kα Inhibitors as Novel Anticancer
Milan Jovanović1,2, Teodora Djikic-Stojsic1, Branislav Stanković3
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia.
Background:
Phosphatidylinositol 3-kinase (PI3K) is a promising anticancer drug target, and selective PI3Kα inhibition may provide both efficacy and an improved safety profile. This study aimed to design new potentially selective PI3Kα inhibitors using computer-aided drug design (CADD).
Methods:
Benzoxazepine and thiazole derivatives were investigated using molecular dynamics, ensemble docking, and Three-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) analyses. Scaffold hopping, substituent replacement, structure-based virtual screening, and density functional theory (DFT) calculations were then applied to guide the design and characterization of new derivatives.
Results:
The study identified new chemotypes capable of interacting with PI3Kα Val851 (αVal851) in the hinge region, including chromeno[3,4-d]imidazole, 2H-benzo[b]oxazine, and quinoline derivatives. Additional substructures directed toward hydrophobic region II and the αGln859 interaction environment supported predicted selectivity over PI3Kβ, PI3Kγ, and PI3Kδ.
Conclusions:
The results establish a comprehensive CADD framework for the rational design of selective PI3Kα inhibitors and provide new compounds with improved predicted selectivity profiles for further development.
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