Identification of Novel PPARα/γ Dual Agonists by Virtual Screening of Specs Database.
Rosiglitazone was restricted clinically due to the side effects such as edema, weight gain and cardiac failure mainly attributing to the single and selective PPARγ activation. Nowadays, multi-targeted PPARs agonists remained to be a hot topic in the antidiabetic medicinal chemistry field. In this paper, the cooperative PPARα/γ dual agonists were screened from Specs database via the flow chart of docking, ADMET prediction and molecular dynamics (MD) simulations. Representative compounds ZINC36517927 and ZINC13573581 displayed higher binding scores, better pharmacokinetic profiles and were predicted to display the best binding affinity with PPARα/γ. Complex-based pharmacophore (CBP) models showed the key interactions in the PPARα/γ active sites. 20 ns simulations performed to the PPAR-ligand complexes indicated a stable binding conformation. This work provided an approach to identify novel high-efficiency PPARα/γ dual agonists for the treatment of type 2 diabetes mellitus (T2DM).
Jun
J
Zhang
Xin
X
Liu
Shu-Qing
SQ
Wang
Jing-Wei
JW
Fu
Wei-Ren
WR
Xu
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China. chengxianchao@aliyun.com.
Xian-Chao
XC
Cheng
Run-Ling
RL
Wang
D001665:Binding Sites; D062126:Databases, Chemical; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D047493:PPAR alpha / Q000819:agonists* / Q000032:analysis; D047495:PPAR gamma / Q000819:agonists* / Q000032:analysis; D011485:Protein Binding; D014584:User-Computer Interface
D008024:Ligands; D047493:PPAR alpha; D047495:PPAR gamma