BACKGROUND The selective targeting of CREB-cAMP-responsive element-binding protein (CBP) has recently evolved as a vital therapeutic approach for curtailing its aberrant upregulation associated with the development of prostate cancer. Inhibition of CBP has been discovered to be an important therapeutic option in androgen receptor signalling pathway mediated prostate cancer. Y08197, a novel selective inhibitor of CBP, has shown promising therapeutic outcome in prostate carcinogenesis over non-selective analogues such as CPI-637. METHODS/RESULTS Herein, we used molecular dynamics simulation to gain insights into the mechanistic and selective targeting of Y08197 at the bromodomain active site. Molecular Mechanics/ Poisson-Boltzmann Surface Area (MM/PBSA) analysis revealed a similar inhibitory effect between Y08197 and CPI-637. Furthermore, in exploring the selective affinity of Y08197 towards CBP in combination with Bromodomain and PHD finger-containing protein 1(BRPF1), our findings highlighted Asp1116 as the 'culprit' residue responsible for this selective targeting. Upon binding, Asp1116 assumed a conformation that altered the architecture of the bromodomain active site, thereby orienting the helices around the active site in a more compacted position. In addition to some specific structural perturbations mediated by Asp1116 on the dynamics of CBP, our study revealed that the strong hydrogen bond interaction (N-H...O) elicited in CBP-Y08197 sequestered Y08197 tightly into the CBP bromodomain active site. CONCLUSION Conclusively, the inhibition and selective pattern of Y08197 can be replicated in future structure-based CBP inhibitors and other bromodomain implicated in carcinogenesis.

中文翻译：

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探索Asp1116在前列腺癌涉及的CREBcAMP反应元件结合蛋白的选择性药物靶向中的作用。

背景技术近来，选择性靶向CREB-cAMP反应性元件结合蛋白（CBP）已成为一种重要的治疗方法，以减少其与前列腺癌的发展有关的异常上调。已经发现抑制CBP是雄激素受体信号传导途径介导的前列腺癌中的重要治疗选择。Y08197是一种新型的CBP选择性抑制剂，与非选择性类似物（如CPI-637）相比，在前列腺癌的治疗中已显示出令人鼓舞的治疗效果。方法/结果本文中，我们使用分子动力学模拟来深入了解Y08197在溴结构域活性位点的机理和选择性靶向。分子力学/泊松玻尔兹曼表面积（MM / PBSA）分析显示，Y08197和CPI-637具有相似的抑制作用。此外，在探索Y08197与Bromodomain和PHD含手指蛋白1（BRPF1）结合时对CBP的选择性亲和力时，我们的发现突出了Asp1116是负责这种选择性靶向的“罪魁祸首”残基。结合后，Asp1116假定其构象改变了溴结构域活性位点的结构，从而使螺旋围绕活性位点定位在更紧密的位置。除了Asp1116对CBP动力学介导的某些特定结构扰动外，我们的研究还揭示了CBP-Y08197中引发的强氢键相互作用（NH ... O）将Y08197紧密地螯合到CBP溴结构域活性位点中。结论最终，