5hrx
Crystal structure of the fifth bromodomain of human PB1 in complex with 1-butylisochromeno[3,4-c]pyrazol-5(2H)-one) compound
Structural highlights
DiseasePB1_HUMAN Defects in PBRM1 are a cause of renal cell carcinoma (RCC) [MIM:144700. It is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into clear cell renal carcinoma (non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma.[1] FunctionPB1_HUMAN Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Acts as a negative regulator of cell proliferation.[2] Publication Abstract from PubMedBromodomains (BRDs) are epigenetic interaction domains currently recognized as emerging drug targets for development of anticancer or anti-inflammatory agents. In this study, development of a selective ligand of the fifth BRD of polybromo protein-1 (PB1(5)) related to switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes is presented. A compound collection was evaluated by consensus virtual screening and a hit was identified. The biophysical study of protein-ligand interactions was performed using X-ray crystallography and isothermal titration calorimetry. Collective data supported the hypothesis that affinity improvement could be achieved by enhancing interactions of the complex with the solvent. The derived SAR along with free energy calculations and a consensus hydration analysis using WaterMap and SZmap algorithms guided rational design of a set of novel analogues. The most potent analogue demonstrated high affinity of 3.3 muM and an excellent selectivity profile, thus comprising a promising lead for the development of chemical probes targeting PB1(5). Discovery and Optimization of a Selective Ligand for the Switch/Sucrose Nonfermenting-Related Bromodomains of Polybromo Protein-1 by the Use of Virtual Screening and Hydration Analysis.,Myrianthopoulos V, Gaboriaud-Kolar N, Tallant C, Hall ML, Grigoriou S, Brownlee PM, Fedorov O, Rogers C, Heidenreich D, Wanior M, Drosos N, Mexia N, Savitsky P, Bagratuni T, Kastritis E, Terpos E, Filippakopoulos P, Muller S, Skaltsounis AL, Downs JA, Knapp S, Mikros E J Med Chem. 2016 Oct 13;59(19):8787-8803. Epub 2016 Sep 27. PMID:27617704[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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