Exploring the Role of Asp1116 in Selective Drug Targeting of CREBcAMP- Responsive Element-binding Protein Implicated...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• CREB-binding protein (CBP) dysregulation is implicated in prostate cancer development.
• Targeting CBP offers a therapeutic strategy for androgen receptor signaling pathway-mediated prostate cancer.
• Y08197 is a novel selective CBP inhibitor demonstrating therapeutic potential in prostate carcinogenesis.

Purpose of the Study:

• To elucidate the mechanistic and selective targeting of Y08197 at the CBP bromodomain active site using molecular dynamics simulations.
• To identify the specific interactions and residues responsible for Y08197's selective binding to CBP, particularly in complex with BRPF1.

Main Methods:

• Molecular dynamics (MD) simulations were employed to analyze the binding interactions of Y08197 with CBP.
• Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) analysis was conducted to assess inhibitory effects.
• Structural analysis focused on identifying key residues and conformational changes within the CBP bromodomain active site.

Main Results:

• MM/PBSA analysis indicated comparable inhibitory effects between Y08197 and the non-selective analogue CPI-637.
• The residue Asp1116 was identified as crucial for the selective targeting of Y08197 towards CBP, especially when complexed with Bromodomain and PHD finger-containing protein 1 (BRPF1).
• Asp1116 binding induced conformational changes in the active site, leading to a more compacted helical structure, and strong hydrogen bonds anchored Y08197 within the CBP bromodomain.

Conclusions:

• The findings provide mechanistic insights into the selective inhibition of CBP by Y08197.
• Asp1116 is a key determinant for the selective binding of Y08197 to CBP.
• The identified inhibition and selectivity pattern of Y08197 can inform the design of future structure-based CBP inhibitors for cancer therapy.