67602-75-9Relevant 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.
Synthesis, 1H NMR Spectral Properties and Conformational Preferences of some Open-chain and Cyclic Aromatic Sulphides Containing Pyridine or 1,3,4-Thiadiazole Units
Bottino, Francesco,Pappalardo, Sebastiano
, p. 1 - 6 (2007/10/02)
The conformational preferences in solution of eight new open-chain and cyclic aromatic sulphides containing pyridine or 1,3,4-thiadiazole units have been investigated, parallel to those of some structurally related phenyl sulphides, by means of 1H NMR spectroscopy.The results obtained have shown that replacement of phenyl by the pyridyl or the 1,3,4-thiadiazolyl moieties induces slightly different propeller arrangements, ascribed to the higher conjugative tendency of both electron-deficient heteroaromatic rings, in all open-chain mixed sulphides, in opposition to the skew arrangements observed for phenyl sulphide derivatives.No prominent differences have been found for cyclic sulphides, which preferentially adopt the sterically unhindered saddle shape conformation.
