Conversion of human-selective PPARalpha agonists to human/mouse dual agonists: a molecular modeling analysis

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 24; pp. 6113 - 6116
• Main Authors: Wang, Minmin, Winneroski, Leonard L, Ardecky, Robert J, Babine, Robert E, Brooks, Dawn A, Etgen, Garret J, Hutchison, Darrell R, Kauffman, Raymond F, Kunkel, Aaron, Mais, Dale E, Montrose-Rafizadeh, Chahrzad, Ogilvie, Kathleen M, Oldham, Brian A, Peters, Mary K, Rito, Christopher J, Rungta, Deepa K, Tripp, Allie E, Wilson, Sarah B, Xu, Yanping, Zink, Richard W, McCarthy, James R
• Format: Journal Article
• Language: English
• Published: England 20.12.2004
• Subjects: Animals; Cinnamates - chemical synthesis; Cinnamates - chemistry; Cinnamates - pharmacology; Drug Design; Humans; Ligands; Mice; Models, Molecular; Molecular Structure; PPAR alpha - agonists; Species Specificity; Structure-Activity Relationship
• ISSN: 0960-894X

To understand the species selectivity in a series of alpha-methyl-alpha-phenoxy carboxylic acid PPARalpha/gamma dual agonists (1-11), structure-based molecular modeling was carried out in the ligand binding pockets of both human and mouse PPARalpha. This study suggested that interaction of both 4-phenoxy and phenyloxazole substituents of these ligands with F272 and M279 in mouse PPARalpha leads to the species-specific divergence in ligand binding. Insights obtained in the molecular modeling studies of these key interactions resulted in the ability to convert a human-selective PPARalpha agonist to a human and mouse dual agonist within the same platform.