Phosphatidylinositol 3-kinase (PI3K) plays a prominent role in regulating various crucial cellular functions. Many studies have indicated the involvement of PI3K in tumorigenesis. In the current study, thirty-one quinazoline derivatives were used to develop a model of Quantitative Structure Activity Relationship (QSAR) which correlates structural feature with PI3K inhibition. The statistically robust QSAR model is pIC50 = 2.515 + 0.000005(AM1_Eele) + 0.004(AM1_HF) + 1.170(AM1_LUMO) ˗ 0.117 (apol) + 0.003(ASA_H) with correlation coefficient, leave-one-out validation coefficient, fischer value, and external validation of R = 0.8572, q2 = 0.6058, F = 16.452, and R2pred=0.7725, respectively. A novel compound (SC25) was proposed based on the validated QSAR model. Molecular docking of ligand on PI3K revealed the similar binding mode of SC25 and parent compound ((S)-C5) as well as native ligand (2NQ). Molecular dynamics simulation of 40 ns confirmed the conformational stability of each SC25, (S)-C5, and 2NQ, complexed with PI3K. Prediction of affinity using MM-PBSA method revealed that SC25 has comparable affinity with that of (S)-C5 and better than that of 2NQ.
Key words: Docking, MM-PBSA, Molecular dynamics simulation, Phosphatidylinositol 3-kinase, QSAR, Quinazoline
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