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Molecular determinants for improved activity at PPARα: structure-activity relationship of pirinixic acid derivatives, docking study and site-directed mutagenesis of PPARα

Lamers, Christina and Dittrich, Michaela and Steri, Ramona and Proschak, Ewgenij and Schubert-Zsilavecz, Manfred. (2014) Molecular determinants for improved activity at PPARα: structure-activity relationship of pirinixic acid derivatives, docking study and site-directed mutagenesis of PPARα. Bioorganic and Medicinal Chemistry Letters, 24 (16). pp. 4048-4052.

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Official URL: https://edoc.unibas.ch/70329/

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Abstract

Peroxisome proliferator-activated receptors (PPARs) are attractive targets for the treatment of the metabolic syndrome. Especially a combination of PPARα and PPARγ agonistic activity seems worthwhile to be pursued. Herein we present the design and synthesis of a series of pirinixic acid derivatives as potent PPARα particularly dual PPARα/γ agonists with 2-((4-chloro-6-((4-(phenylamino)phenyl)amino)pyrimidin-2-yl)thio)octanoicacid having the highest potential. Our investigations based on molecular docking and structure-activity relationship (SAR) studies elucidated structural determinants affecting the potency at PPARα. A diphenylamine-scaffold seems to play a key role. Careful in silico analysis revealed an essential role for a hydrogen bond between the diphenylamine and a water cluster. We confirmed this hypothesis using a mutated PPARα LBD in our transactivation assay to disrupt the water cluster and to validate the proposed interaction.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ricklin)
UniBasel Contributors:Lamers, Christina
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Elsevier
ISSN:0960-894X
e-ISSN:1464-3405
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:16 Nov 2020 10:46
Deposited On:16 Nov 2020 10:46

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