Τίτλος:
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
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Bromodomains (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 μM and an excellent selectivity profile, thus comprising a promising lead for the development of chemical probes targeting PB1(5). © 2016 American Chemical Society.
Συγγραφείς:
Myrianthopoulos, V.
Gaboriaud-Kolar, N.
Tallant, C.
Hall, M.-L.
Grigoriou, S.
Brownlee, P.M.
Fedorov, O.
Rogers, C.
Heidenreich, D.
Wanior, M.
Drosos, N.
Mexia, N.
Savitsky, P.
Bagratuni, T.
Kastritis, E.
Terpos, E.
Filippakopoulos, P.
Müller, S.
Skaltsounis, A.-L.
Downs, J.A.
Knapp, S.
Mikros, E.
Περιοδικό:
Journal of Medicinal Chemistry
Εκδότης:
American Chemical Society
Λέξεις-κλειδιά:
1 butylisochromeno[3,4 c]pyrazol 5(2h) one; 1 ethylisochromeno[3,4 c]pyrazol 5(2h) one; 1 methylisochromeno[3,4 c]pyrazol 5(2h) one; 1 propylisochromeno[3,4 c]pyrazol 5(2h) one; antineoplastic agent; bromodomain inhibitor; polybromo protein 1; synapsin I; unclassified drug; ligand; molecular library; nuclear protein; PBRM1 protein, human; protein binding; transcription factor, algorithm; Article; cell viability; chromatin assembly and disassembly; consensus; controlled study; drug screening; drug synthesis; human; hydration; hydrogen bond; in vitro study; isothermal titration calorimetry; nucleophilicity; protein domain; protein expression; X ray crystallography; antagonists and inhibitors; cell line; chemistry; computer simulation; drug design; drug effects; metabolism; molecular library; molecular model; pharmacology; protein domain; structure activity relation, Cell Line; Computer Simulation; Crystallography, X-Ray; Drug Design; Humans; Ligands; Models, Molecular; Nuclear Proteins; Protein Binding; Protein Domains; Small Molecule Libraries; Structure-Activity Relationship; Transcription Factors
DOI:
10.1021/acs.jmedchem.6b00355
