Komati Rajesh, Spadoni Dominick, Zheng Shilong, Sridhar Jayalakshmi, Riley Kevin E, Wang Guangdi
Department of Chemistry and RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA.
Molecules. 2017 Jan 5;22(1):88. doi: 10.3390/molecules22010088.
Liver X receptors (LXRs) have been increasingly recognized as a potential therapeutic target to treat pathological conditions ranging from vascular and metabolic diseases, neurological degeneration, to cancers that are driven by lipid metabolism. Amidst intensifying efforts to discover ligands that act through LXRs to achieve the sought-after pharmacological outcomes, several lead compounds are already being tested in clinical trials for a variety of disease interventions. While more potent and selective LXR ligands continue to emerge from screening of small molecule libraries, rational design, and empirical medicinal chemistry approaches, challenges remain in minimizing undesirable effects of LXR activation on lipid metabolism. This review provides a summary of known endogenous, naturally occurring, and synthetic ligands. The review also offers considerations from a molecular modeling perspective with which to design more specific LXRβ ligands based on the interaction energies of ligands and the important amino acid residues in the LXRβ ligand binding domain.
肝脏X受体（LXRs）越来越被认为是一种潜在的治疗靶点，可用于治疗从血管和代谢疾病、神经退行性变到由脂质代谢驱动的癌症等一系列病理状况。在为发现通过LXRs起作用以实现理想药理结果的配体而不断加大努力的过程中，几种先导化合物已在针对多种疾病干预的临床试验中进行测试。虽然从小分子文库筛选、合理设计和经验性药物化学方法中不断涌现出更有效和更具选择性的LXR配体，但在将LXR激活对脂质代谢的不良影响降至最低方面仍存在挑战。本综述总结了已知的内源性、天然存在的和合成配体。该综述还从分子建模的角度提供了一些考虑因素，以便基于配体的相互作用能和LXRβ配体结合域中的重要氨基酸残基来设计更具特异性的LXRβ配体。
