Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS

New computational model for the interaction between retinoids/rexinoids and their nuclear receptors (RAR/RXR) taking into account the solvation

Ligand recognition to retinoic receptors (RXRa and RAR) has been studied using a molecular mechanics-based docking method. The protocol is able to rank the affinity of the ligands for a single retinoid receptor, the highest values corresponding to those that adapt better to the shape of the binding site and generate the optimal set of electrostatic and van der Waals interactions with the receptor.

Moreover, our studies shed light into some of the energetic contributions to retinoid receptor ligand selectivity. In this regard we show that there is a difference in polarity between the binding site regions that anchor the carboxylate in RAR and RXR, which translates itself in large differences in interaction energy of both receptors for the same ligand. We observe that the latter energy change is cancelled off by the solvation energy penalty upon binding.

This energy compensation is borne out as well by experiments that address the effect of site directed mutagenesis in ligand binding to RAR. The hypothesis that the difference in binding site polarity might be exploited to build RXR selective ligands is tested with some compounds having a thiazolidinedione anchoring group.

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Reported by

Departamento de Química Orgánica
Facultade de Química, Departamento de Química Orgánica, Campus As Lagoas Marcosende
36310 Vigo
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