Journal Article

PUBDB-2024-05632

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png ChemEM: Flexible Docking of Small Molecules in Cryo-EM Structures

Sweeney, A.CSSB* ; Mulvaney, T.CSSB* ; Maiorca, M.Extern*CSSB* ; Topf, M. (Corresponding author)Extern*CSSB*

2023
ACS Washington, DC

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Please use a persistent id in citations: doi:10.1021/acs.jmedchem.3c01134  doi:10.3204/PUBDB-2024-05632

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 high-resolution 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 well-established 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.

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Contributing Institute(s):

1. CSSB - Leibniz-Institut für Experimentelle Virologie (LIV) / UKE - Maya Topf (CSSB-LIV/UKE-MT)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Experiment(s):

1. No specific instrument

Appears in the scientific report 2023

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Database coverage:
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