用于调节视黄酸X受体（RXR）功能的配体设计

Ligand Design for Modulation of RXR Functions.

作者信息

Martínez Claudio, Souto José A, de Lera Angel R

机构信息

Departamento de Química Orgánica, Facultade de Química, CINBIO and IBIV, Universidade de Vigo, Vigo, Spain.

出版信息

Methods Mol Biol. 2019;2019:51-72. doi: 10.1007/978-1-4939-9585-1_4.

DOI:10.1007/978-1-4939-9585-1_4

PMID:31359388

Abstract

Retinoid X receptors (RXRs) are promiscuous partners of heterodimeric associations with other members of the Nuclear Receptor (NR) superfamily. RXR ligands ("rexinoids") either transcriptionally activate the "permissive" subclass of heterodimers or synergize with partner ligands in the "nonpermissive" subclass of heterodimers. The rationale for rexinoid design with a wide structural diversity going from the structures of existing complexes with RXR determined by X-Ray, to natural products and other ligands discovered by high-throughput screening (HTS), mere serendipity, and rationally designed based on Molecular Modeling, will be described. Included is the new generation of ligands that modulate the structure of specific receptor surfaces that serve to communicate with other regulators. The panel of the known RXR agonists, partial (ant)agonists, and/or heterodimer-selective rexinoids require the exploration of their therapeutic potential in order to overcome some of the current limitations of rexinoids in therapy.

摘要

维甲酸X受体（RXRs）是与核受体（NR）超家族其他成员形成异源二聚体的混杂伴侣。RXR配体（“视黄酸类化合物”）要么转录激活异源二聚体的“允许性”亚类，要么在异源二聚体的“非允许性”亚类中与伴侣配体协同作用。将描述视黄酸类化合物设计的基本原理，其结构多样性广泛，从通过X射线确定的与RXR的现有复合物结构，到通过高通量筛选（HTS）发现的天然产物和其他配体，纯粹是偶然发现，以及基于分子建模合理设计的。其中包括新一代配体，它们可调节特定受体表面的结构，这些表面用于与其他调节因子进行通讯。已知的RXR激动剂、部分（反）激动剂和/或异源二聚体选择性视黄酸类化合物需要探索其治疗潜力，以克服目前视黄酸类化合物在治疗中的一些局限性。