Straightforward hit identification approach in fragment-based discovery of bromodomain-containing protein 4 (BRD4) inhibitors |
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Authors: | Petro Borysko Yurii S. Moroz Oleksandr V. Vasylchenko Vasyl V. Hurmach Anastasia Starodubtseva Natalia Stefanishena Kateryna Nesteruk Sergey Zozulya Ivan S. Kondratov Oleksandr O. Grygorenko |
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Affiliation: | 1. Bienta/Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine;2. Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine;3. National Taras Shevchenko University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine;4. Institute of Bioorganic Chemistry and Petrochemistry, National Ukrainian Academy of Science, Murmanska St. 1, Kyiv 02660, Ukraine |
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Abstract: | A combination approach of a fragment screening and “SAR by catalog” was used for the discovery of bromodomain-containing protein 4 (BRD4) inhibitors. Initial screening of 3695-fragment library against bromodomain 1 of BRD4 using thermal shift assay (TSA), followed by initial hit validation, resulted in 73 fragment hits, which were used to construct a follow-up library selected from available screening collection. Additionally, analogs of inactive fragments, as well as a set of randomly selected compounds were also prepared (3?×?3200 compounds in total). Screening of the resulting sets using TSA, followed by re-testing at several concentrations, counter-screen, and TR-FRET assay resulted in 18 confirmed hits. Compounds derived from the initial fragment set showed better hit rate as compared to the other two sets. Finally, building dose-response curves revealed three compounds with IC50?=?1.9–7.4?μM. For these compounds, binding sites and conformations in the BRD4 (4UYD) have been determined by docking. |
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Keywords: | Fragment-based drug discovery SAR by catalog Thermal shift assay Epigenetic targets Bromodomains |
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