Structural features of quercetin derivatives by using pharmaco-phore modeling approach

Quercetin is a natural occurring flavonoid. Quercetin exerts a direct pro-apoptotic effect on tumor cells by blocking the growth of several cancer cell lines at different phases of the cell cycle. Quercetin derivatives have attracted considerable attention for their cytotoxicity against human cancer cell lines. This project was aimed for pharmacophore mapping of NSCLC cells by focusing on finding the structure of the receptor. The compounds were of natural origin, which are known to act on the NSCLC protein and there are notable references of such compounds in scholarly literature. Then their interaction with EGFR was studied to find one of the best potential targets. Hence, we have shown a pharmacophore based 3D QSAR study of Quercetin derivatives that are aimed at inhibiting EGFR protein. Most of the molecules proved to be effective in terms of their binding score, the best score being -9.66028 and the binding energy value, -74.45. From the 50 hypotheses obtained from Phase methodology, a robust pharmacophore model was developed statistically, the best hypothesis was obtained by calculating the regression coefficient (R2) for each, taking into consideration their experimental and predicted IC50 values and also taking into account their fitness and validating them using statistical calculations. The R2 value for both the training and test sets were significant for the hypothesis AAARR.1386. This pharmacophore was identified to have pharmacophore features, namely, 3 hydrogen bond acceptors and 2 aromatic rings. Thus, such a pharmacophore model provides insights into the structural and chemical features of the EGFR inhibitors of Quercetin derivatives and these compounds can be used as effective inhibitors of NSCLC cell growth. The features of the receptor, obtained from the pharmacophore model can be used in further studies to understand the molecular mechanism behind specific cancer types.

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