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

作者：Myrianthopoulos Vassilios; Gaboriaud Kolar Nicolas; Tallant Cynthia; Hall Michelle Lynn; Grigoriou Stylianos; Brownlee Peter Moore; Fedorov Oleg; Rogers Catherine; Heidenreich David; Wanior Marek; Drosos Nikolaos; Meda Nikitia; Savitsky Pavel; Bagratuni Tina; Kastritis Efstathios; Terpos Evangelos; Filippakopoulos Panagis; Mueller Susanne; Skaltsounis Alexios Leandros; Downs Jessica Ann; Knapp Stefan; Mikros Emmanuel

来源：Journal of Medicinal Chemistry, 2016, 59(19): 8787-8803.

DOI：10.1021/acs.jmedchem.6b00355

Bromodomain (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(S)) 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 mu M and an excellent selectivity profile, thus comprising a promising lead for the development of chemical probes targeting PB1(5).

• 出版日期2016-10-13