Exploring the Inhibitory Efficacy of Resokaempferol and Tectochrysin on PI3Kα Protein by Combining DFT and Molecular Docking against Wild-Type and H1047R Mutant Forms

This study explores the inhibitory potential of the flavonoids resokaempferol and tectochrysin against both wild-type and H1047R mutant forms of PI3Kα, aiming to expand the repertoire of targeted cancer therapies. Employing an array of computational techniques, including Density Functional Theory (DFT), calculations of electronic parameters such as the energies of the frontier molecular orbitals, Molecular Electrostatic Potential (MEP) mapping, and Molecular Docking, we investigate in detail the molecular interactions of these compounds with the PI3Kα kinase. Our findings, corroborated by DFT calculations performed based on the B3LYP (Becke, three-parameter, Lee-Yang-Parr) hybrid functional and the 6-311G++(d,p) basis set, align well with experimental benchmarks and indicate substantial inhibitory efficacy. Further analysis of chemical potential and bioavailability confirmed the drug-like attributes of these flavonoids. Binding affinity and selectivity were rigorously assessed through self-docking and cross-docking against the PIK3CA PDB structures 7K71 and 8TS9. The most promising interactions were validated using Pairwise Structure Alignment and MolProbity analysis of all-atom contacts and geometry. Collectively, these results highlight the flavonoids’ potential as PI3Kα inhibitors and exemplify the utility of natural compounds in the development of precise anticancer treatments.