The use of phosphopeptides and phosphor compounds to inhibitor the breast-cancer−associated protein 1 (BRCA1) C-terminal (BRCT) repeats, which is involved in the DNA repair pathway, has been an attractive strategy for cancer treatment. It's of great interest to develop high affinity small-molecule BRCT inhibitors. In this study, we investigated the interaction between BRCT domain and multiple phosphopeptides and phosphor compounds with computational methods. We performed molecular dynamics (MD) simulations to investigate the promiscuous binding affinity of BRCT domain. MD results revealed the key role of receptor hinge motion as well as flexibility distribution of receptor active site in its promiscuous binding affinity. We used Mining minima (M2) method for thorough conformational search and computing binding free energy. Molecular Mechanics Poisson−Boltzmann Surface Area Method (MM/PBSA) was also carried out to explore conformational fluctuations for BRCT and ligands in different states. Our calculations agreed with experimental data. Based on findings from the computational work, we optimized the ligand by introducing new interactions between ligand and receptor. We found that instead of pre-rigidifying ligand, design a flexible ligand with multiple bound conformations might be an effective alternative to reduce entropy cost, which provided a new strategy for drug design.

Free-energy calculations for ligand/phosphopeptide and BRCT domain binding

251st National Meeting (2016)

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