82P - Applying computational approaches to build a predictive protein structure and discover novel inhibitors for mitotic serine/threonine kinase BUB1B

Background

Prostate cancer patients often develop resistance to androgen deprivation therapy, leading to castration-resistant prostate cancer (CRPC). This resistance is associated with constitutively active androgen receptor variants (AR-Vs), driving disease progression. Through meta-analysis, our lab identified 7 oncogenic genes interacting with AR variants, including BUB1B. Currently, no crystal structure exists for BUB1B's kinase domain, nor a suitable small molecule inhibitor. Thus, we aim to develop an ATP-competitive inhibitor targeting BUB1B, potentially offering a new CRPC therapy.

Methods

In this study, we conducted homology modeling to generate a high-quality structure of BUB1B. We optimized our approach by selectively filtering protein models based on their adherence to Ramachandran plot criteria and their ability to maintain correct conformations in the ligand binding pocket. Our focus was on developing a robust protein structure suitable for subsequent molecular docking studies. The small molecule compounds selected for docking were derived from a Multi-Task Deep Neural Network trained to predict inhibitors targeting BUB1B, leveraging bioactivity data across multiple kinase targets.

Results

Based on our docking studies, we have identified several promising small molecule inhibitors for BUB1B through computational simulations. These inhibitors demonstrated favorable docking scores, indicating strong potential for binding affinity. Furthermore, they were subjected to rigorous validation using MM-GBSA analysis, redocking experiments, and docking simulations with and without magnesium ions to assess stability and robustness of binding interactions.

Conclusions

In conclusion, our study successfully identified promising small molecule inhibitors for BUB1B. Moving forward, validation using ADP-Glo assays will provide crucial experimental confirmation of their activity. These findings underscore the potential of these compounds as therapeutic candidates for addressing castration-resistant prostate cancer.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

University of Miami.

Disclosure

The authors have declared no conflicts of interest.