2023Sweeney ChemEM

Citation

Sweeney, Aaron / Mulvaney, Thomas / Maiorca, Mauro / Topf, Maya. ChemEM: Flexible Docking of Small Molecules in Cryo-EM Structures. 2023. J. Medicinal Chemistry, Vol. 67, No. 1, p. 199-212

Abstract

Cryo-electron microscopy (cryo-EM), through resolution advancements, has become pivotal in structure-based drug discovery. However, most cryo-EM structures are solved at 3−4 Å resolution, posing challenges for small-molecule docking and structure-based virtual screening due to issues in the precise positioning of ligands and the surrounding side chains. We present ChemEM, a software package that employs cryo-EM data for the accurate docking of one or multiple ligands in a protein-binding site. Validated against a highly curated benchmark of high- and medium-resolution cryo-EM structures and the corresponding highresolution controls, ChemEM displayed impressive performance, accurately placing ligands in all but one case, often surpassing cryo- EM PDB-deposited solutions. Even without including the cryo-EM density, the ChemEM scoring function outperformed the wellestablished AutoDock Vina score. Using ChemEM, we illustrate that valuable information can be extracted from maps at medium resolution and underline the utility of cryo-EM structures for drug discovery.

Links

https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.3c01134