Discovery of novel estrogen-related receptor α inverse agonists by virtual screening and biological evaluation

Zhao, Hui; Lin, Chi‐Feng; Hu, Kai-Wen; Wen, Xiaoan; Yuan, Haoliang

doi:10.1080/07391102.2018.1462736

Cited by 5 publications

(4 citation statements)

References 15 publications

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“…Most recently, a novel ERRα inverse agonist has been identified by virtual screening and biological evaluation. In this study, (E)-4-chloro-N-(4-oxo-3-(m-tolylamino)naphthalen-1(4H)-ylidene)benzenesulfonamide significantly inhibited ERRα-induced genes and showed moderate anti-proliferative activity against both the ER-positive and ERnegative breast cancer lines (H. Zhao, Lin, Hu, Wen, & Yuan, 2019).…”

Section: Small Molecule Modulators Of Errsmentioning

confidence: 81%

International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily—Update 2023

Burris,

de Vera,

Cote

et al. 2023

Pharmacol Rev

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Section: Small Molecule Modulators Of Errsmentioning

confidence: 81%

International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily—Update 2023

Burris,

de Vera,

Cote

et al. 2023

Pharmacol Rev

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“…Various groups over the years have employed these CADD tools for finding novel inhibitors from available databases and experimentally testing the best hits to validate their findings. Virtual Screening (VS) studies have been conducted for the discovery of ligands for the ERα-EBS pocket [208][209][210][211][212][213][214][215] and for all subtypes of ER [209,210,[216][217][218][219][220][221][222].…”

Section: Selective Estrogen Receptor Modulators (Serms)mentioning

confidence: 99%

Computer-Aided Ligand Discovery for Estrogen Receptor Alpha

Bafna

Ban

Rennie

et al. 2020

IJMS

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Breast cancer (BCa) is one of the most predominantly diagnosed cancers in women. Notably, 70% of BCa diagnoses are Estrogen Receptor α positive (ERα+) making it a critical therapeutic target. With that, the two subtypes of ER, ERα and ERβ, have contrasting effects on BCa cells. While ERα promotes cancerous activities, ERβ isoform exhibits inhibitory effects on the same. ER-directed small molecule drug discovery for BCa has provided the FDA approved drugs tamoxifen, toremifene, raloxifene and fulvestrant that all bind to the estrogen binding site of the receptor. These ER-directed inhibitors are non-selective in nature and may eventually induce resistance in BCa cells as well as increase the risk of endometrial cancer development. Thus, there is an urgent need to develop novel drugs with alternative ERα targeting mechanisms that can overcome the limitations of conventional anti-ERα therapies. Several functional sites on ERα, such as Activation Function-2 (AF2), DNA binding domain (DBD), and F-domain, have been recently considered as potential targets in the context of drug research and discovery. In this review, we summarize methods of computer-aided drug design (CADD) that have been employed to analyze and explore potential targetable sites on ERα, discuss recent advancement of ERα inhibitor development, and highlight the potential opportunities and challenges of future ERα-directed drug discovery.

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“…The results suggested that PPARα might be a potential therapeutic target for NASH. This promoted us to find novel PPARα agonists through virtual screening, especially molecular docking, which has been prevalently applied in lead discovery and drug design. − Biological evaluation and mechanistic studies on the hit compounds were performed, leading to the discovery of compound A-4 . MD simulation − was used to reveal the key residues and stable binding mode for compound A-4 .…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Peroxisome Proliferator-Activated Receptor α (PPARα) Agonists by Virtual Screening and Biological Evaluation

Dai

Feng

Zha

et al. 2020

J. Chem. Inf. Model.

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Nonalcoholic steatohepatitis (NASH) is one of the important causes of cirrhosis and hepatocellular carcinoma worldwide. PPARα is highly expressed in the liver and plays a critical role in hepatic lipid metabolism. Our analysis of the gene expression profiles in the liver of humanized mice treated with a PPARα agonist and NASH patients suggested that PPARα might be a potential target for NASH therapy. This promoted us to find novel PPARα agonists. The results of virtual screening and biological evaluation identified compound A-4 as a selective PPARα agonist. It significantly regulated the target genes of PPARα involved in fatty acid metabolism and inflammation, exhibiting cellular anti-inflammatory activity. The key residues involved in the binding between PPARα ligand-binding domain (LBD) and compound A-4 were revealed by molecular dynamics (MD) simulation and further experimentally validated by the mutation study. Together, compound A-4 was well characterized as a novel lead compound for developing potent and selective PPARα agonists.

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Discovery of novel estrogen-related receptor α inverse agonists by virtual screening and biological evaluation

Cited by 5 publications

References 15 publications

International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily—Update 2023

International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily—Update 2023

Computer-Aided Ligand Discovery for Estrogen Receptor Alpha

Discovery of Novel Peroxisome Proliferator-Activated Receptor α (PPARα) Agonists by Virtual Screening and Biological Evaluation

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