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 utilized to build a Quantitative Structure-Activity Relationship (QSAR) model 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 a leave-one-out cross-validation coefficient (q2) of 0.6058 and external validation (R2pred) of 0.7725. A novel compound (SC25) was proposed based on the validated QSAR model. Molecular docking of the 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 a comparable affinity with that of (S)-C5 and better than that of 2NQ.
Arba M, Ruslin, Kalsum WU, Alroem A, Muzakkar MZ, Usman I, Tjahjono DH. QSAR, Molecular Docking and Dynamics Studies of Quinazoline Derivatives as Inhibitor of Phosphatidylinositol 3-Kinase. J App Pharm Sci, 2018; 8(05): 001-009.
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