257876-07-6Relevant academic research and scientific papers
Chemical validation of a druggable site on Hsp27/HSPB1 using in silico solvent mapping and biophysical methods
Makley, Leah N.,Johnson, Oleta T.,Ghanakota, Phani,Rauch, Jennifer N.,Osborn, Delaney,Wu, Taia S.,Cierpicki, Tomasz,Carlson, Heather A.,Gestwicki, Jason E.
, (2021/02/09)
Destabilizing mutations in small heat shock proteins (sHsps) are linked to multiple diseases; however, sHsps are conformationally dynamic, lack enzymatic function and have no endogenous chemical ligands. These factors render sHsps as classically “undruggable” targets and make it particularly challenging to identify molecules that might bind and stabilize them. To explore potential solutions, we designed a multi-pronged screening workflow involving a combination of computational and biophysical ligand-discovery platforms. Using the core domain of the sHsp family member Hsp27/HSPB1 (Hsp27c) as a target, we applied mixed solvent molecular dynamics (MixMD) to predict three possible binding sites, which we confirmed using NMR-based solvent mapping. Using this knowledge, we then used NMR spectroscopy to carry out a fragment-based drug discovery (FBDD) screen, ultimately identifying two fragments that bind to one of these sites. A medicinal chemistry effort improved the affinity of one fragment by ~50-fold (16 μM), while maintaining good ligand efficiency (~0.32 kcal/mol/non-hydrogen atom). Finally, we found that binding to this site partially restored the stability of disease-associated Hsp27 variants, in a redox-dependent manner. Together, these experiments suggest a new and unexpected binding site on Hsp27, which might be exploited to build chemical probes.
Utilization of an Active Site Mutant Receptor for the Identification of Potent and Selective Atypical 5-HT2C Receptor Agonists
Carpenter, Joseph,Wang, Ying,Wu, Gang,Feng, Jianxin,Ye, Xiang-Yang,Morales, Christian L.,Broekema, Matthias,Rossi, Karen A.,Miller, Keith J.,Murphy, Brian J.,Wu, Ginger,Malmstrom, Sarah E.,Azzara, Anthony V.,Sher, Philip M.,Fevig, John M.,Alt, Andrew,Bertekap, Robert L.,Cullen, Mary Jane,Harper, Timothy M.,Foster, Kimberly,Luk, Emily,Xiang, Qian,Grubb, Mary F.,Robl, Jeffrey A.,Wacker, Dean A.
, p. 6166 - 6190 (2017/08/02)
Agonism of the 5-HT2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT2C. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C with high selectivity over the related 5-HT2A and 5-HT2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT2C antagonist.
Thiazoles as inhibitors of 11B-hydroxysteroid dehydrogenase
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Page/Page column 12, (2008/06/13)
Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, type II diabetes mellitus and metabolic syndrome.
