A novel strategy for designing the selective PPAR agonist by the "sum of activity" model

Journal of Biomolecular Structure & Dynamics
Hung-Jin HuangCalvin Yu-Chian Chen

Abstract

Peroxisome proliferator-activated receptors alpha, delta and gamma are a collection of ligand-activated transcription factors crucial in lipid and glucose homeostasis. The involvement of these receptors in lipid metabolism makes them perfect therapeutic target for treating obesity and stroke. In this study, 'sum of activity' model was employed to design multi-target agonists. We used a new strategy to design agonists that fit both alpha and delta but not gamma, to avoid side effect. The CoMFA and CoMSIA models were used to explore the pharmacophore features by constructing three individual models: (a) alpha-model, (b) delta-model and (c) gamma-model, and two sum models: (d) alpha, delta- model, and (e) alpha, delta and gamma-model. The CoMFA model yielded a significant cross validation value, q(2), of 0.729 and non-cross validation value, r(2), of 0.933 in the alpha, delta-model. The CoMSIA studies yielded the best predictive models with q(2) of 0.622 in A+S and with r(2) of 0.911 in the alpha, delta-model. Finally, we proposed that distinct features shown in models (a), (b), (d) but not (c) and (e) should be accounted in designing weight-controlling drugs.

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Citations

Jun 24, 2011·Journal of Biomolecular Structure & Dynamics·Deok-Soo KimJong Bhak
Feb 8, 2011·Journal of Biomolecular Structure & Dynamics·Ankita PunethaDurai Sundar
Feb 8, 2011·Journal of Biomolecular Structure & Dynamics·Tung-Ti ChangCalvin Yu-Chian Chen
Apr 8, 2011·Journal of Biomolecular Structure & Dynamics·Maliheh S AtriAmir Niasari-Naslaji
May 11, 2012·Journal of Biomolecular Structure & Dynamics·Calvin Yu-Chian Chen
Jun 15, 2012·Journal of Biomolecular Structure & Dynamics·Weng Ieong Tou, Calvin Yu-Chian Chen
Jun 13, 2012·Journal of Biomolecular Structure & Dynamics·Mahdi AlijanianzadehAli Akbar Moosavi-Movahedi
Jun 27, 2012·Journal of Biomolecular Structure & Dynamics·Kuan-Chung ChenCalvin Yu-Chian Chen
Aug 15, 2012·Journal of Biomolecular Structure & Dynamics·Ming LiuYouyong Li
Nov 8, 2012·Chest·Nicholas J Gross
Aug 2, 2011·Chemical Biology & Drug Design·Kuan-Chung ChenCalvin Yu-Chian Chen
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May 31, 2014·Evidence-based Complementary and Alternative Medicine : ECAM·Kuan-Chung ChenCalvin Yu-Chian Chen
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Aug 20, 2014·BioMed Research International·Kuan-Chung ChenCalvin Yu-Chian Chen
Jul 23, 2014·BioMed Research International·Kuen-Bao ChenCalvin Yu-Chian Chen
Aug 31, 2011·Journal of Biomolecular Structure & Dynamics·Aline A OliveiraTanos C C França
Jun 24, 2011·Journal of Biomolecular Structure & Dynamics·Huan-Zhang XieSheng-Yong Yang
Apr 8, 2011·Journal of Biomolecular Structure & Dynamics·Teodorico C RamalhoElaine F F da Cunha
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Aug 31, 2011·Journal of Biomolecular Structure & Dynamics·Adeleh DivsalarRamaswamy H Sarma
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Aug 30, 2014·Journal of Computer-aided Molecular Design·Veronica M W GeeChun Wei Yap
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