6286-30-2Relevant articles and documents
Sudborough, J. J.,Thomas, J.
, p. 715 (1910)
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.
Synthesis method of o-Dibromo compound
-
Paragraph 0042-0051, (2022/01/04)
The present invention discloses a synthesis method of o-dibromo compounds, said synthesis method comprising the following steps: preparation of olefins, brominated salts and a mixed solution of bromate; to the mixed solution of dropwise addition of hydrochloric acid solution for reaction; to the end of the reaction, the extraction of o-dibromo compounds in the reaction product; the synthesis method to inexpensive brominated salts (industrial or recycled brominated salts) and bromate as a bromine source, enhance the full use of applicable resources; after the end of the reaction after a simple filtration treatment to obtain a sufficient purity of the product, It can reduce production costs; at the same time, facilitate the transportation and storage of raw materials, and improve the working environment. The synthesis method of the present invention is simple and easy to operate, high safety, small pollution, simple post-treatment, low production cost, product yield and purity can meet the production needs, is both cost advantages and safety and environmental advantages of the industrializable process.
