Structure-based drug design of a novel family of PPARgamma partial agonists: virtual screening, X-ray crystallography, and in vitro/in vivo biological activities.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is well-known as the receptor of thiazolidinedione antidiabetic drugs. In this paper, we present a successful example of employing structure-based virtual screening, a method that combines shape-based database search with a docking study and analogue search, to discover a novel family of PPARgamma agonists based upon pyrazol-5-ylbenzenesulfonamide. Two analogues in the family show high affinity for, and specificity to, PPARgamma and act as partial agonists. They also demonstrate glucose-lowering efficacy in vivo. A structural biology study reveals that they both adopt a distinct binding mode and have no H-bonding interactions with PPARgamma. The absence of H-bonding interaction with the protein provides an explanation why both function as partial agonists since most full agonists form conserved H-bonds with the activation function helix (AF-2 helix) which, in turn, enhances the recruitment of coactivators. Moreover, the structural biology and computer docking studies reveal the specificity of the compounds for PPARgamma could be due to the restricted access to the binding pocket of other PPAR subtypes, i.e., PPARalpha and PPARdelta, and steric hindrance upon the ligand binding.
Lu
I-Lin
IL
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Taipei, Taiwan, ROC.
Huang
Chien-Fu
CF
Peng
Yi-Hui
YH
Lin
Ying-Ting
YT
Hsieh
Hsing-Pang
HP
Chen
Chiung-Tong
CT
Lien
Tzu-Wen
TW
Lee
Hwei-Jen
HJ
Mahindroo
Neeraj
N
Prakash
Ekambaranellore
E
Yueh
Andrew
A
Chen
Hsin-Yi
HY
Goparaju
Chandra M V
CM
Chen
Xin
X
Liao
Chun-Chen
CC
Chao
Yu-Sheng
YS
Hsu
John T-A
JT
Wu
Su-Ying
SY
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D047495:PPAR gamma / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D014158:Transcription, Genetic / Q000235:genetics
D008024:Ligands; D047495:PPAR gamma