Structural basis for the improved potency of peroxisome proliferator-activated receptor (PPAR) agonists.
The need to develop safer and more effective antidiabetic drugs is essential owing to the growth worldwide of the diabetic population. Targeting the PPAR receptor is one strategy for the treatment of diabetes; the PPAR agonists rosiglitazone and pioglitazone are already on the market. Here we report the identification of a potent PPAR agonist, 15, whose PPARγ activation was more than 20 times better than that of rosiglitazone. Compound 15 was designed to incorporate an indole head with a carboxylic acid group, and 4-phenylbenzophenone tail to achieve a PPARγ EC(50) of 10 nM. Compound 15 showed the most potent PPARγ agonist activity among the compounds we investigated. To gain molecular insight into the improved potency of 15, a structural biology study and binding energy calculations were carried out. Superimposition of the X-ray structures of 15 and agonist 10 revealed that, even though they have the same indole head part, they adopt different conformations. The head part of 15 showed stronger interactions toward PPARγ; this could be due to the presence of the novel tail part 4-phenylbenzophenone, which could enhance the binding efficiency of 15 to PPARγ.
Peng
Yi-Hui
YH
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
Coumar
Mohane Selvaraj
MS
Leou
Jiun-Shyang
JS
Wu
Jian-Sung
JS
Shiao
Hui-Yi
HY
Lin
Chia-Hui
CH
Lin
Wen-Hsing
WH
Lien
Tzu Wen
TW
Chen
Xin
X
Hsu
John T-A
JT
Chao
Yu-Sheng
YS
Huang
Chien-Fu
CF
Lyu
Ping-Chiang
PC
Hsieh
Hsing-Pang
HP
Wu
Su-Ying
SY
D001577:Benzophenones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D006860:Hydrogen Bonding; D007210:Indoleacetic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D045162:Thiazolidinediones / Q000737:chemistry
C555046:(5-(3-(4-(biphenyl-4-ylcarbonyl)phenoxy)propoxy)-1H-indol-1-yl)acetic acid; D001577:Benzophenones; D007210:Indoleacetic Acids; D007211:Indoles; D047495:PPAR gamma; D045162:Thiazolidinediones; C047723:benzophenone; C030374:indole