title: Conversion of human-selective PPARalpha agonists to human/mouse dual agonists: a molecular modeling analysis.
abstract: 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.
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN 46285, USA. wang_minmin@lilly.com
authors.forename: Minmin
authors.initials: M
authors.lastname: Wang
authors.forename: Leonard L
authors.initials: LL
authors.lastname: Winneroski
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ardecky
authors.forename: Robert E
authors.initials: RE
authors.lastname: Babine
authors.forename: Dawn A
authors.initials: DA
authors.lastname: Brooks
authors.forename: Garret J
authors.initials: GJ
authors.lastname: Etgen
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Hutchison
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Kauffman
authors.forename: Aaron
authors.initials: A
authors.lastname: Kunkel
authors.forename: Dale E
authors.initials: DE
authors.lastname: Mais
authors.forename: Chahrzad
authors.initials: C
authors.lastname: Montrose-Rafizadeh
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Ogilvie
authors.forename: Brian A
authors.initials: BA
authors.lastname: Oldham
authors.forename: Mary K
authors.initials: MK
authors.lastname: Peters
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rito
authors.forename: Deepa K
authors.initials: DK
authors.lastname: Rungta
authors.forename: Allie E
authors.initials: AE
authors.lastname: Tripp
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Wilson
authors.forename: Yanping
authors.initials: Y
authors.lastname: Xu
authors.forename: Richard W
authors.initials: RW
authors.lastname: Zink
authors.forename: James R
authors.initials: JR
authors.lastname: McCarthy
mesh_terms: D000818:Animals; D002934:Cinnamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D047493:PPAR alpha / Q000819:agonists*; D013045:Species Specificity; D013329:Structure-Activity Relationship
chemical_list: D002934:Cinnamates; D008024:Ligands; D047493:PPAR alpha