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Probing biological activity through structural modelling of ligand-receptor interactions of 2,4-disubstituted thiazole retinoids

Lookup NU author(s): Hesham Haffez, Dr Natalie TatumORCiD, Dr Chris RedfernORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Retinoids, such as all-trans-retinoic acid (ATRA), regulate cellular differentiation and signalling pathways in chordates by binding to nuclear retinoic acid receptors (RARα/β/γ). Polar interactions between receptor and ligand are important for binding and facilitating the non-polar interactions and conformational changes necessary for RAR-mediated transcriptional regulation. The constraints on activity and RAR-type specificity with respect to the structural link between the polar and non-polar functions of synthetic retinoids are poorly understood. To address this, predictions from in silico ligand-RAR docking calculations and molecular dynamics simulations for a small library of stable, synthetic retinoids (designated GZ series) containing a central thiazole linker structure and different hydrophobic region substituents, were tested using a ligand bindingassay and a range of cellular biological assays. The docking analysis showed that these thiazole-containing retinoids were well suited to the binding pocket of RARα, particularly via a favorable hydrogen bonding interaction between the thiazole and Ser232 of RARα. A bulky hydrophobic region (i.e., present in compounds GZ23 and GZ25) was important for interaction with the RAR binding pockets. Ligand binding assays generally reflected the findings from in silicodocking, and showed that GZ25 was a particularly strongly binding ligand for RARα/β. GZ25 also exhibited higher activity as an inducer of neuronal differentiation than ATRA and other GZ derivatives. These data demonstrate that GZ25 is a stable synthetic retinoid with improved activity which efficiently regulates neuronal differentiation and help to define the key structural requirements for retinoid activity enabling the design and development of the next generation of more active, selective synthetic retinoids as potential therapeutic regulators of neurogenesis.

Publication metadata

Author(s): Haffez H, Chisholm DR, Tatum NJ, Valentine R, Redfern C, Pohl E, Whiting A, Przyborski S

Publication type: Article

Publication status: Published

Journal: Bioorganic & Medicinal Chemistry

Year: 2018

Volume: 26

Issue: 8

Pages: 1560-1572

Print publication date: 01/05/2018

Online publication date: 10/02/2018

Acceptance date: 02/02/2018

Date deposited: 01/05/2018

ISSN (print): 0968-0896

ISSN (electronic): 1464-3391

Publisher: Pergamon Press


DOI: 10.1016/j.bmc.2018.02.002

PubMed id: 29439915


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Funder referenceFunder name
C2115/A21421Cancer Research UK CRUK (closed comp)