Discovery of CREBBP bromodomain inhibitors by high-throughput docking and hit optimization guided by molecular dynamics

Xu, Min; Unzue, Andrea; Dong, Jing; Spiliotopoulos, Dimitrios; Nevado, Cristina; Caflisch, Amedeo

doi:10.1021/acs.jmedchem.5b00171

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Xu, M., Unzue, A., Dong, J., Spiliotopoulos, D., Nevado, C., & Caflisch, A. (2015). Discovery of CREBBP bromodomain inhibitors by high-throughput docking and hit optimization guided by molecular dynamics. Journal of Medicinal Chemistry, 2487–2491. https://doi.org/10.1021/acs.jmedchem.5b00171

Abstract

We have identified two chemotypes of CREBBP bromodomain ligands by fragment-based high-throughput docking. Only 17 molecules from the original library of two-million compounds were tested in vitro. Optimization of the two low-micromolar hits, the 4-acylpyrrole 1 and acylbenzene 9, was driven by molecular dynamics results which suggested improvement of the polar interactions with the Arg1173 side chain at the rim of the binding site. The synthesis of only two derivatives of 1 yielded the 4-acylpyrrole 6 which shows a single-digit micro