Rational design and structure–activity relationship studies of quercetin–amino acid hybrids targeting the anti-apoptotic protein Bcl-xL

N HSQC NMR chemical shift perturbation mapping was used to chart the binding site of the quercetin analogues in the Bcl-xL that overlapped with the predicted poses generated by both IFD and MD calculations. Furthermore, evaluation of the four conjugates against the prostate DU-145 and PC-3 cancer cell lines, revealed quercetin-glutamic acid and quercetin-alanine as the most potent conjugates bearing the higher cytostatic activity. This pinpoints that the chemical space of natural products can be tailored to exploit new hits for difficult tractable targets such as protein-protein interactions.