Author/Authors :
Minmin Wang، نويسنده , , Leonard L. Winneroski، نويسنده , , Robert J. Ardecky، نويسنده , , Robert E. Babine، نويسنده , , Dawn A. Brooks، نويسنده , , Garret J. Etgen، نويسنده , , Darrell R. Hutchison، نويسنده , , Raymond F. Kauffman، نويسنده , , Aaron Kunkel، نويسنده , , Dale E. Mais، نويسنده , , Chahrzad Montrose-Rafizadeh، نويسنده , , Kathleen M. Ogilvie، نويسنده , , Brian A. Oldham، نويسنده , , Mary K. Peters، نويسنده , , Christopher J. Rito، نويسنده , , Deepa K. Rungta، نويسنده , , Allie E. Tripp، نويسنده , , Sarah B. Wilson، نويسنده , , Yanping Xu، نويسنده , , Richard W. Zink، نويسنده , , et al.، نويسنده ,
Abstract :
To understand the species selectivity in a series of α-methyl-α-phenoxy carboxylic acid PPARα/γ dual agonists (1–11), structure-based molecular modeling was carried out in the ligand binding pockets of both human and mouse PPARα. This study suggested that interaction of both 4-phenoxy and phenyloxazole substituents of these ligands with F272 and M279 in mouse PPARα 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 PPARα agonist to a human and mouse dual agonist within the same platform.
Keywords :
PPARa agonist , Species selectivity , Structure-based design.* Corresponding authors. Tel.: +1 317 433 9621 , fax: +1 317 276 5431(M.W.) , tel.: +1 317 277 2216 , fax: +1 317 277 2035 (L.L.W.) , tel.: +1317 433 1345 , fax: +1 317 276 5431 (J.R.M.) , e-mail addresses:wang_minmin@lilly.com , lwinneroski@lilly.com , jmccarthy@lilly.com
