Homology modeling of human BAP1 and analysis of its binding properties through molecular docking and molecular dynamics simulation

BRCA1-associated protein 1 (BAP1) is a nuclear-localized Ubiquitin C-terminal hydrolase (UCH) that functions as a tumour suppressor, and although BAP1 has been linked to cancer, the molecular mechanism by which BAP1 regulates cancer and its crystal structure have not been elucidated. In this study, computational approaches were used to identify the protein model of BAP1 and its potential inhibitors. The structure of the BAP1 model was constructed through homology modeling and the generated BAP1 model was observed to exhibit good quality protein model as the distribution of its amino acids in the Ramachandran's plot corresponded to 87.7% in the most favoured regions. Docking and simulating of the ubiquitin on the BAP1 model structure revealed the rearrangement of F228, F50, and H169 residues of the BAP1 and switching of BAP1's conformation into a productive state. Our screening results of potential BAP1 inhibitors against the FDA approved drugs shortlisted two potential inhibitors, which are FDA1065 and FDA755. We then performed molecular dynamics simulations and Molecular mechanics Poisson-Boltzmann surface area (MMPBSA) analysis on both inhibitors and found that only the BAP1-FDA755 formed a stable complex and the FDA755 ligand remained its position inside the active site of the BAP1 with a total binding energy of (-51.77 +/- 3.49 kcal/mol). We speculate that the presence of methyl group in FDA755 play an important role in stabilizing the BAP1-FDA755 complex. Communicated by Ramaswamy H. Sarma