Howard Flack Crystallographic Lectures Series 2021/6

We have developed a program for the docking of libraries of fragments (molecules with a molecular weight smaller than 300 g/mol) that makes use of a force field energy-evaluation with an implicit model of the solvent. By means of high-throughput docking we have identified small-molecule inhibitors of six human bromodomains, protein modules that bind acetylated histone tails. In the case of the CREBBP bromodomain, optimization of the initial hits by chemical synthesis of derivatives has resulted in several low-nanomolar binders with favorable ligand efficiency and high selectivity against other bromodomains. Thus, the screening of fragment libraries by docking is very efficient (24,000 molecules in a day on a commodity desktop) and the hit rate, i.e., the number of active molecules among the purchased compounds, is very high (typically 10% to 30%). We have validated the predicted binding modes by solving the crystal structure of about 150 bromodomain/ligand complexes. Two lead compounds for the CREBBP bromodomain and the Ephrin tyrosine kinases, respectively, have shown antiproliferative activity in mouse xenograft models.