Pharmacophore Modeling, 3D-QSAR and Docking studies on Quinazoline antifolate Thymidylate Synthase Inhibitors

Kumari, Kotni Meena; Vijjulatha, Manga
January 2012
Journal of Pharmacy Research;2012, Vol. 5 Issue 1, p304
Academic Journal
Thymidylate synthase (TS) is a crucial enzyme for DNA biosynthesis and many nonclassical lipophilic antifolates targeting this enzyme are quite efficient and encouraging as antitumor drugs. We report 3D-QSAR analyses by Pharmacophore modeling on quinazoline antifolates in order to have a better understanding of the mechanism of action and structure-activity relationship of these compounds. Five point Pharmacophore with one hydrogen bond acceptor (A), one hydrogen bond donor (D), one hydrophobic group (H), one negatively ionizable group (N) and one aromatic ring (R) as pharmacophoric features was developed. Amongst them the pharmacophore hypothesis ADHNR 326 yielded statistically significant 3D-QSAR model with 0.917 as R² value and 0.607 as Q² value, was considered to be the best pharmacophore hypothesis. The developed Pharmacophore model was validated by predicting the activity of test set molecules and external test set molecules. The squared predictive correlation coefficient of 0.788 and 0.854 was observed between experimental and predicted activity values of test set and external test set of molecules respectively. The results obtained from this study can be used for rational design of potent inhibitors against thymidylate synthase.


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