Exploring the Role of Asp1116 in Selective Drug Targeting of CREB-cAMP- Responsive Element-binding Protein Implicated in Prostate Cancer

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 center dot center dot center dot 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.