Advances and Challenges in Drug Design of PPAR delta Ligands

Author(s)

Maltarollo, Vinicius Goncalves ^{[1, 2, 3]} ; Kronenberger, Thales ^{[4, 5]} ; Windshuegel, Bjoern ^[4] ; Wrenger, Carsten ^[5] ; Goulart Trossini, Gustavo Henrique ^[1] ; Honorio, Kathia Maria ^{[6, 2]}

Affiliation

^[1] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Pharm, Sao Paulo, SP - Brazil

^[2] Fed Univ ABC UFABC, Ctr Human & Nat Sci, Santo Andre, SP - Brazil

^[3] Fed Univ Minas Gerais UFMG, Fac Pharm, Dept Pharmaceut Prod, Av Antonio Carlos 6627, BR-31270901 Belo Horizonte, MG - Brazil

^[4] Fraunhofer Inst Mol Biol & Appl Ecol IME, Schnackenburgallee 114, D-22525 Hamburg - Germany

^[5] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Unit Drug Discovery, Av Prof Lineu Prestes 1374, BR-05508000 Sao Paulo, SP - Brazil

^[6] Univ Sao Paulo, Sch Arts Sci & Humanities, Sao Paulo, SP - Brazil

• Document type: Review article
• Source: CURRENT DRUG TARGETS; v. 19, n. 2, p. 144-154, 2018.
• Web of Science Citations: 1

Abstract

Background: Peroxisome proliferator-activated receptors (PPAR) are nuclear receptors activated by endogenous fatty acids and prostaglandins that are classified into three types: alpha, gamma and delta, 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 PPAR alpha (fibrates) and PPAR gamma (glitazones), but up to now there is none clinically used drug targeting PPAR delta. Additionally, several side-effects associated with the use of PPAR alpha and gamma agonists are reported by regulatory agencies, which do not indicate anymore their use as first-line drugs. Objective: A significant new market has grown in the last years, focusing on the development of new PPAR delta agonists as drug candidates to treat metabolic diseases and, in this sense, this study proposes to review the structural requirements to achieve selective PPAR delta 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 PPAR delta. Conclusion: Several PPAR delta 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 PPAR delta binding site as well as the importance of substituent and some physicochemical properties that could help to design of new classes of agonists. (AU)

• FAPESP's process: 14/03644-9 - Targeting alternative ligand-binding sites in nuclear receptors using computational and experimental screening
• Grantee: Thales Kronenberger
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/27313-1 - Targeting alternative ligand-binding sites in nuclear receptors using computational and experimental screening
• Grantee: Thales Kronenberger
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate