Abstract
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 binding assay 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 silico docking, 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.
Highlights
Retinoids are signaling molecules functionally related to alltrans retinoic acid (ATRA), a metabolite of Vitamin A (Fig. 1).[1,2] These small lipophilic molecules mediate cellular proliferation, differentiation and homeostasis in chordates[3] by acting as ligands for Abbreviations: ATRA, all-trans retinoic acid; AF, activation function; ESI, electronic supplementary information; GZ, compound series code; H12, helix 12; ligand-binding domain (LBD), ligand binding domain; retinoic acid receptors (RARs), retinoic acid receptor; retinoic acid response elements (RAREs), retinoic acid response element; retinoid X receptors (RXRs), retinoid X receptor; TTN, 1,1,4,4-tetramethyl-1,2,3,4tetrahydronaphthalene hydrophobic region.durham.ac.uk
Members of a family of nuclear receptors referred to as retinoic acid receptors (RARs) and retinoid X receptors (RXRs)
This involved an initial, semi-empirical calculation of the conformational distribution of each compound to indicate the low energy conformations that the ligand can adopt, and to provide starting points for the molecular docking calculations used to predict the possible binding modes when complexed with the RAR LBDs
Summary
Retinoids are signaling molecules functionally related to alltrans retinoic acid (ATRA), a metabolite of Vitamin A (Fig. 1).[1,2] These small lipophilic molecules mediate cellular proliferation, differentiation and homeostasis in chordates[3] by acting as ligands for Abbreviations: ATRA, all-trans retinoic acid; AF, activation function; ESI, electronic supplementary information; GZ, compound series code; H12, helix 12; LBD, ligand binding domain; RAR, retinoic acid receptor; RARE, retinoic acid response element; RXR, retinoid X receptor; TTN, 1,1,4,4-tetramethyl-1,2,3,4tetrahydronaphthalene hydrophobic region.durham.ac.uk Given the range of biological processes regulated by retinoids, there is huge potential for synthetic retinoids as therapeutics. This potential has yet to be realized, mainly because of a lack of detailed understanding of RAR signaling mechanisms in biological processes and the design criteria for targeting synthetic retinoids to specific responses.
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