Conversion of human-selective PPARalpha agonists to human/mouse dual agonists: a molecular modeling analysis.
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.
Wang
Minmin
M
Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN 46285, USA. wang_minmin@lilly.com
Winneroski
Leonard L
LL
Ardecky
Robert J
RJ
Babine
Robert E
RE
Brooks
Dawn A
DA
Etgen
Garret J
GJ
Hutchison
Darrell R
DR
Kauffman
Raymond F
RF
Kunkel
Aaron
A
Mais
Dale E
DE
Montrose-Rafizadeh
Chahrzad
C
Ogilvie
Kathleen M
KM
Oldham
Brian A
BA
Peters
Mary K
MK
Rito
Christopher J
CJ
Rungta
Deepa K
DK
Tripp
Allie E
AE
Wilson
Sarah B
SB
Xu
Yanping
Y
Zink
Richard W
RW
McCarthy
James R
JR
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
D002934:Cinnamates; D008024:Ligands; D047493:PPAR alpha