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The demand for allosteric targeting of nuclear receptors is high, but examples are limited, and structural information is scarce. The retinoic acid-related orphan receptor gamma t (RORγt) is an important transcriptional regulator for the differentiation of T helper 17 cells for which the first, and some of the most promising, examples of allosteric nuclear receptor modulation have been reported and structurally proven. In a 2015 patent, filed by the pharmaceutical company Glenmark, a new class of small molecules was reported that act as potent inverse agonists for RORγt. A compound library around the central thienopyrazole scaffold captured a clear structure-activity relationship, but the binding mechanism of this new class of RORγt modulators has not been elucidated. Using a combination of biochemical and X-ray crystallography studies, here the allosteric mechanism for the inverse agonism for the most potent compound, classified in the patent as "example 13", is reported, providing a strongly desired additional example of allosteric nuclear receptor targeting.
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Retinoic acid receptor-related orphan receptor γt (RORγt) is a nuclear receptor associated with the pathogenesis of autoimmune diseases. Allosteric inhibition of RORγt is conceptually new, unique f...
This paper describes the behavior of binding and functional receptor systems where an antagonist of the receptor/G protein binding reaction is added as a blocker of agonist-induced receptor function. ...
To determine if diminished orthosteric agonist binding due to mutations in extracellular loops 1 or 2 of the cannabinoid receptor 1 (CB ) can be overcome by an allosteric modulator and restore agonist...
Cannabinoid 1 receptor (CB1R) allosteric ligands hold far-reaching therapeutic promise. We report application of fluoro- and nitrogen-walk approaches to enhance the drug-like properties of GAT211, a p...
Allostery is considered one of the most direct and efficient ways to regulate biological macromolecule functions. Allostery is increasingly receiving attention in the field of drug discovery because o...
Meclizine hydrochloride is an antihistamine widely used for treatment of vertigo and motion sickness. In HCC it has been used for anti-emetic effects, but it is used here as a CAR (constit...
To test the hypothesis that 11-15 week treatment with the inverse agonist nadolol will improve smoking cessation in patients with chronic cough associated with long-term smoking, with or w...
This trial is conducted in the United States. The aim of this clinical trial is to investigate whether chronic liraglutide administration affects the mode of action (pharmacokinetics) of i...
The study test whether the NSAID allosteric site of human sulfotransferase 1A1 (SULT1A1) is operative in humans. The study will test the effects of mefenamic acid (MEF) on the sulfonation ...
This is a multicenter open-label mode of action study. Twenty patients with moderate to severe hidradenitis suppurativa will be treated with guselkumab 200 mg Q4W subcutaneously. Main obje...
Phenomena and pharmaceutics of compounds that bind to the same receptor binding-site as an agonist (DRUG AGONISM) for that receptor but exerts the opposite pharmacological effect.
The first mixed agonist-antagonist analgesic to be marketed. It is an agonist at the kappa and sigma opioid receptors and has a weak antagonist action at the mu receptor. (From AMA Drug Evaluations Annual, 1991, p97)
Phenomena and pharmaceutics of compounds that inhibit the function of agonists (DRUG AGONISM) and inverse agonists (DRUG INVERSE AGONISM) for a specific receptor. On their own, antagonists produce no effect by themselves to a receptor, and are said to have neither intrinsic activity nor efficacy.
A guanidinium antihypertensive agent that acts by blocking adrenergic transmission. The precise mode of action is not clear.
A mode of communication concerned with inducing or urging the adoption of certain beliefs, theories, or lines of action by others.