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

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).

溴结构域（Bromodomains, BRDs）是一类表观遗传相互作用结构域，目前已成为开发抗癌或抗炎药物的新兴药物靶点。本研究报道了与SWI/SNF（switch/sucrose nonfermenting）染色质重塑复合物相关的多溴蛋白1第五个溴结构域（PB1(5)）的选择性配体开发工作。研究通过共识虚拟筛选对化合物库进行评估，成功获得命中化合物。采用X射线晶体学与等温滴定量热法，开展了蛋白-配体相互作用的生物物理研究。综合实验数据验证了“通过增强复合物与溶剂的相互作用可提升亲和力”这一假说。所得构效关系（Structure-Activity Relationship, SAR）、自由能计算结果，以及结合WaterMap与SZmap算法的共识水化分析，指导了一系列新型衍生物的合理设计。其中活性最强的衍生物展现出3.3 μM的高亲和力与优异的选择性谱，成为靶向PB1(5)的化学探针开发的极具潜力的先导化合物。