Dataset Information

Identification of PPARgamma partial agonists of natural origin (I): development of a virtual screening procedure and in vitro validation.

ABSTRACT:

Background

Although there are successful examples of the discovery of new PPAR? agonists, it has recently been of great interest to identify new PPAR? partial agonists that do not present the adverse side effects caused by PPAR? full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPAR? partial agonists among natural products.

Methodology/principal findings

We have developed a virtual screening procedure based on structure-based pharmacophore construction, protein-ligand docking and electrostatic/shape similarity to discover novel scaffolds of PPAR? partial agonists. From an initial set of 89,165 natural products and natural product derivatives, 135 compounds were identified as potential PPAR? partial agonists with good ADME properties. Ten compounds that represent ten new chemical scaffolds for PPAR? partial agonists were selected for in vitro biological testing, but two of them were not assayed due to solubility problems. Five out of the remaining eight compounds were confirmed as PPAR? partial agonists: they bind to PPAR?, do not or only moderately stimulate the transactivation activity of PPAR?, do not induce adipogenesis of preadipocyte cells and stimulate the insulin-induced glucose uptake of adipocytes.

Conclusions/significance

We have demonstrated that our virtual screening protocol was successful in identifying novel scaffolds for PPAR? partial agonists.

SUBMITTER: Guasch L

PROVIDER: S-EPMC3511273 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Identification of PPARgamma partial agonists of natural origin (I): development of a virtual screening procedure and in vitro validation.

Guasch Laura L Sala Esther E Castell-Auví Anna A Cedó Lidia L Liedl Klaus R KR Wolber Gerhard G Muehlbacher Markus M Mulero Miquel M Pinent Montserrat M Ardévol Anna A Valls Cristina C Pujadas Gerard G Garcia-Vallvé Santiago S

PloS one 20121130 11

<h4>Background</h4>Although there are successful examples of the discovery of new PPARγ agonists, it has recently been of great interest to identify new PPARγ partial agonists that do not present the adverse side effects caused by PPARγ full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPARγ partial agonists among natural products.<h4>Methodology/principal findings</h4>We have developed a virtual screening procedur ...[more]

PMID: 23226391

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Project description:BackgroundThere has been great interest in determining whether natural products show biological activity toward protein targets of pharmacological relevance. One target of particular interest is DPP-IV whose most important substrates are incretins that, among other beneficial effects, stimulates insulin biosynthesis and secretion. Incretins have very short half-lives because of their rapid degradation by DPP-IV and, therefore, inhibiting this enzyme improves glucose homeostasis. As a result, DPP-IV inhibitors are of considerable interest to the pharmaceutical industry. The main goals of this study were (a) to develop a virtual screening process to identify potential DPP-IV inhibitors of natural origin; (b) to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits; and (c) to use the most active hit for predicting derivatives with higher binding affinities for the DPP-IV binding site.Methodology/principal findingsWe predicted that 446 out of the 89,165 molecules present in the natural products subset of the ZINC database would inhibit DPP-IV with good ADMET properties. Notably, when these 446 molecules were merged with 2,342 known DPP-IV inhibitors and the resulting set was classified into 50 clusters according to chemical similarity, there were 12 clusters that contained only natural products for which no DPP-IV inhibitory activity has been previously reported. Nine molecules from 7 of these 12 clusters were then selected for in vitro activity testing and 7 out of the 9 molecules were shown to inhibit DPP-IV (where the remaining two molecules could not be solubilized, preventing the evaluation of their DPP-IV inhibitory activity). Then, the hit with the highest activity was used as a lead compound in the prediction of more potent derivatives.Conclusions/significanceWe have demonstrated that our virtual-screening protocol was successful in identifying novel lead compounds for developing more potent DPP-IV inhibitors.

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Dataset Information

Identification of PPARgamma partial agonists of natural origin (I): development of a virtual screening procedure and in vitro validation.

Background

Methodology/principal findings

Conclusions/significance

Publications

Identification of PPARgamma partial agonists of natural origin (I): development of a virtual screening procedure and in vitro validation.

Similar Datasets

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