Advances and Challenges in Drug Design of PPARδ Ligands

药品 计算生物学 药理学 计算机科学 医学 化学 生物
作者
Vinícius Gonçalves Maltarollo,Thales Kronenberger,Björn Windshügel,Carsten Wrenger,Gustavo Henrique Goulart Trossini,Káthia Maria Honório
出处
期刊:Current Drug Targets [Bentham Science]
卷期号:19 (2): 144-154 被引量:11
标识
DOI:10.2174/1389450118666170414113159
摘要

Peroxisome proliferator-activated receptors (PPAR) are nuclear receptors activated by endogenous fatty acids and prostaglandins that are classified into three types: α, γ and δ, which have different functions and tissue distribution. PPAR modulators have been exploited to the treatment of important metabolic diseases, such as type 2 diabetes mellitus and metabolic syndrome, which are considered relevant epidemic diseases currently. Along the last decades, several studies have reported structural differences between the three PPAR subtypes associated with the discovery of selective ligands, dual and pan-agonists. Nowadays, there are several approved drugs that activate PPARα (fibrates) and PPARγ (glitazones), but up to now there is none clinically used drug targeting PPARδ. Additionally, several side-effects associated with the use of PPARα and γ agonists are reported by regulatory agencies, which do not indicate anymore their use as first-line drugs.A significant new market has grown in the last years, focusing on the development of new PPARδ agonists as drug candidates to treat metabolic diseases and, in this sense, this study proposes to review the structural requirements to achieve selective PPARδ activation, as well to discuss the most relevant agonists in clinical trials, providing information on the current phase in the drug discovery and design targeting PPARδ.Several PPARδ ligands with high potency were reported in the literature and were designed or discovered by a combination of experimental and computational approaches. Furthermore, the reported importance of pockets and individual residues at PPARδ binding site as well as the importance of substituent and some physicochemical properties that could help to design of new classes of agonists.
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