In-silico investigation of CREB-binding protein on castration-resistant prostrate cancer: insight from molecular dynamic simulations and computer aided drug discovery.

Abstract

Prostate cancer has evolved over the years despite various treatment and therapy. One recent threat of the prostate cancer is the Castration- Resistant Prostate Cancer (CRPC). The CRPC is an advanced form of prostate cancer. Despite therapies involving chemical, surgical or hormonal treatment, the cancer cells in CRPC have been discovered to continue growth and development at an alarming rate. This forms the basis for this research. One novel drug (Y08197) aimed towards CBRB-binding protein was reported to have anti- cancer properties and therapeutic effect on CRPC. Their research based on in vivo and in vitro experiments, revealed CREB-binding protein as a therapeutic target. This study majored in a search for the culprit behind this miracle. We used molecular dynamics simulation to gain insights into the mechanistic and selective targeting of the novel drug as well as its similar inhibitory effect to an FDA drug (CPI-637). Also, since little is known about the structural and inhibitory properties of CREB-binding protein, we also commenced a review study to look into its inhibitory history. The use of computational techniques such as molecular modeling, molecular docking, virtual screening protocols and molecular dynamics allows the evaluation and assessment of potential leads compounds. These in-silico techniques as stated above are cost-effective and efficient in research and pivot to fast track drug discovery process. 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 result highlighted Asp1116 as the ‘culprit’ residue responsible for this selective targeting. Conclusively, the implementation of the information extracted in this study, can be replicated in future structure based CBP inhibitors and pharmacological research implicated in carcinogenesis.