Activity landscape modeling of PPAR ligands with dual-activity difference maps

Bioorganic & Medicinal Chemistry
Oscar Méndez-LucioJ L Medina-Franco

Abstract

Activation of peroxisome proliferator-activated receptor (PPAR) subtypes offers a promising strategy for the treatment of diabetes mellitus and metabolic diseases. Selective and dual PPAR agonists have been developed and the systematic characterization of their structure-activity relationships (SAR) is of major significance. Herein, we report a systematic description of the SAR of 168 compounds screened against the three PPAR subtypes using the principles of activity landscape modeling. As part of our effort to develop and apply chemoinformatic tools to navigate through activity landscapes, we employed consensus dual-activity difference maps recently reported. The analysis is based on pairwise relationships of potency difference and structure-similarity which were calculated from the combination of four different 2D and 3D structure representations. Dual-activity difference maps uncovered regions in the landscape with similar SAR for two or three receptor subtypes as well as regions with inverse SAR, that is, changes in structure that increase activity for one subtype but decrease activity for the other subtype. Analysis of pairs of compounds with high structure similarity revealed the presence of single-, dual-, and 'pan-recep...Continue Reading

References

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Citations

May 28, 2013·Journal of Chemical Information and Modeling·José L Medina-FrancoRichard A Houghten
Nov 28, 2013·Future Medicinal Chemistry·Rodrigo Aguayo-OrtizJosé L Medina-Franco
Aug 14, 2012·Chemical Biology & Drug Design·Jaime Pérez-VillanuevaRafael Castillo
Aug 28, 2014·Drug Development Research·Vicente F Kuyoc-Carrillo, José L Medina-Franco
Jul 8, 2015·Molecular Diversity·Jaime Pérez-VillanuevaJosé L Medina-Franco
Feb 25, 2014·Drug Discovery Today·Maykel Cruz-MonteagudoFernanda Borges
Feb 1, 2013·Molecular Informatics·Jaime Pérez-VillanuevaJosé L Medina-Franco
Dec 1, 2012·Molecular Informatics·Oscar Méndez-LucioJosé L Medina-Franco
Jan 24, 2015·Journal of Chemical Information and Modeling·Oscar Méndez-LucioJosé L Medina-Franco

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