Structure-based identification of novel PPAR gamma ligands

Zhang

et al. 2014

DDDT

The thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPARγ) agonists are restricted in clinical use as antidiabetic agents because of side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPARγ is the main cause of these side effects. Multitargeted PPARα/γ/δ pan agonist development is the hot topic in the antidiabetic drug research field. In order to identify PPARα/γ/δ pan agonists, a compound database was established by core hopping of rosiglitazone, which was then docked into a PPARα/γ/δ active site to screen out a number of candidate compounds with a higher docking score and better interaction with the active site. Further, absorption, distribution, metabolism, excretion, and toxicity prediction was done to give eight compounds. Molecular dynamics simulation of the representative Cpd#1 showed more favorable binding conformation for PPARs receptor than the original ligand. Cpd#1 could act as a PPARα/γ/δ pan agonist for novel antidiabetic drug research.

Section: Methodsmentioning

confidence: 99%

Identification of novel multitargeted PPARα/γ/δ pan agonists by core hopping of rosiglitazone

Zhang

et al. 2014

DDDT

“…The docking scoring energies are calculated all-at-once rather than via small perturbations that are central to techniques, such as free energy perturbation and alchemical thermodynamic integration, that can at least pretend to the calculation of relative and absolute affinities of binding. Over a calculation that samples 10 7 candidate ligands in 10 13 configurations, any one of these terms could ensure the failure of a docking screen for plausible ligands.…”

Section: Docking and Its Discontentsmentioning

confidence: 99%

Docking Screens for Novel Ligands Conferring New Biology

2016

It is now plausible to dock libraries of 10 million molecules against targets over several days or weeks. When the molecules screened are commercially available, they may be rapidly tested to find new leads. Although docking retains important liabilities (it cannot calculate affinities accurately nor even reliably rank order high-scoring molecules), it can often can distinguish likely from unlikely ligands, often with hit rates above 10%. Here we summarize the improvements in libraries, target quality, and methods that have supported these advances, and the open access resources that make docking accessible. Recent docking screens for new ligands are sketched, as are the binding, crystallographic, and in vivo assays that support them. Like any technique, controls are crucial, and key experimental ones are reviewed. With such controls, docking campaigns can find ligands with new chemotypes, often revealing the new biology that may be docking’s greatest impact over the next few years.

Journal of the Brazilian Chemical Society

“…Whereas pioglitazone and rosiglitazone are still marketed, however, recent studies indicated that rosiglitazone is associated with body weight gain, increased risk of myocardial infarction and death from cardiovascular causes. [12][13][14] These adverse effects are related to the selective activation of PPARγ. The literature also presents results of drugs that are able to activate concomitantly PPARα, PPARβ/δ and PPARγ, this combined activation was able to avoid the adverse effects caused by the PPARγ selective activation.…”

Section: Introductionmentioning

confidence: 99%

“…These effects also prevents the formation of atherosclerotic plaques and therefore reduces cardiovascular risks. 14,19 Moreover, the effects associated with selective activation of PPARγ, such as the weight gain, are not observed. 20 Some PPAR pan agonists have entered clinical trials and show a promising field of research in the development of new drugs to treat metabolic syndrome.…”

Section: Introductionmentioning

confidence: 99%

New PPARα/γ/δ Optimal Activator Rationally Designed by Computational Methods

Padilha

Serafim

Sarmiento

et al. 2016

The peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that acts as a transcription factor, regulating glucose, lipid and inflammation signaling and it is exploited in type 2 diabetes treatment. However, the selective activation of this PPAR subtype has been linked to important adverse effects which can be mitigated through concomitant activation of PPARα and PPARδ. In this study, we proposed new PPARγ agonists using PharmaGist Server for pharmacophore prediction, the molecular docking was performed by GOLD (genetic optimization for ligand docking) v2.2, AutoDock 4.2 and AutoDock Vina 1.1 and QikProp v4.0 and Derek for absorption, distribution, metabolism, excretion and toxicity (ADMET) assessment. One molecule showed high predicted affinity to PPARγ and favorable pharmacokinetic and toxicity properties. It was then evaluated against PPARα and PPARδ and showed greater affinity to these receptors than the controls. Therefore this molecule is a promising drug lead for the development of derivatives and for the treatment of metabolic syndrome with the benefits of a PPAR pan activation.Keywords: type 2 diabetes, PPAR pan agonist, molecular modeling, ADMET prediction IntroductionThe general cause of mortality among type 2 diabetes mellitus patients is due to dyslipidemia leading to cardiovascular complications. Currently, the drugs used to control these disorders act separately either on reducing blood glucose or lowering triglyceride levels, free fatty acid and low-density lipoprotein. However, the increasing number of cases of patients with diabetic metabolic syndrome requires the development of therapies that act simultaneously reducing glicidic and lipidic levels in a combined effort to ease cardiovascular disorders. 1 Peroxisome proliferatoractivated receptors (PPARs) are nuclear receptors that act as transcription factors, regulating glucose homeostasis, lipid metabolism and inflammation signaling, making them attractive targets for the development of new therapies for metabolic syndromes. They regulate the expression of target genes after forming a heterodimer with 9-cis-retinoic acid receptor (RXR) and bind to the peroxisome proliferators response elements (PPRE) in the regulatory region of the target gene. The increased transcriptional rates of their target genes may be increased after interaction with an agonist ligand which alters the conformation of PPAR, exposing the DNA (deoxyribonucleic acid) binding site. Three distinct receptors have already been described, PPARα, PPARδ and PPARγ. 2 Padilha et al. 1637 Vol. 27, No. 9, 2016 PPARγ plays an important role in the regulation of glucose and lipid metabolism and it is widely distributed in adipose tissue. 3,4 In adipocytes, the PPARγ activity regulates the expression of genes involved in lipid metabolism, 5-7 in addition to the control of the expression of proteins involved in the uptake of lipids by adipocytes. 8 The PPARγ activation in adipose tissue presents an indirect activity in tissues which respond to insulin. 9 This e...