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Issue 37, 2017
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Rational design and structure–activity relationship studies of quercetin–amino acid hybrids targeting the anti-apoptotic protein Bcl-xL

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Abstract

Anti-apoptotic proteins, like the Bcl-2 family proteins, present an important therapeutic cancer drug target. Their activity is orchestrated through neutralization upon interaction of pro-apoptotic protein counterparts that leads to immortality of cancer cells. Therefore, generating compounds targeting these proteins is of immense therapeutic importance. Herein, Induced Fit Docking (IFD) and Molecular Dynamics (MD) simulations were performed to rationally design quercetin analogues that bind in the BH3 site of the Bcl-xL protein. IFD calculations determined their binding cavity while Molecular Mechanics Poisson Boltzmann Surface Area (MM-PBSA) and Molecular Mechanics Generalised Born Surface Area (MM-GBSA) calculations provided an insight into the binding enthalpies of the analogues. The quercetin analogues were synthesized and their binding to Bcl-xL was verified with fluorescence spectroscopy. The binding affinity and the thermodynamic parameters between Bcl-xL and quercetin-glutamic acid were estimated through Isothermal Titration Calorimetry. 2D 1H–15N 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.

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

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Publication details

The article was received on 17 Aug 2017, accepted on 07 Sep 2017 and first published on 07 Sep 2017


Article type: Paper
DOI: 10.1039/C7OB02045G
Citation: Org. Biomol. Chem., 2017,15, 7956-7976
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    Rational design and structure–activity relationship studies of quercetin–amino acid hybrids targeting the anti-apoptotic protein Bcl-xL

    T. F. Kellici, M. V. Chatziathanasiadou, M. Lee, N. Sayyad, E. G. Geromichalou, E. I. Vrettos, A. D. Tsiailanis, S. Chi, G. D. Geromichalos, T. Mavromoustakos and A. G. Tzakos, Org. Biomol. Chem., 2017, 15, 7956
    DOI: 10.1039/C7OB02045G

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