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Issue 7, 2019
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Binding site characterization – similarity, promiscuity, and druggability

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Abstract

The elucidation of non-obvious binding site similarities has provided useful indications for the establishment of polypharmacology, the identification of potential off-targets, or the repurposing of known drugs. The concept underlying all of these approaches is promiscuous binding which can be analyzed from a ligand-based or a binding site-based perspective. Herein, we applied methods for the automated analysis and comparison of protein binding sites to study promiscuous binding on a novel dataset of sites in complex with ligands sharing common shape and physicochemical properties. We show the suitability of this dataset for the benchmarking of novel binding site comparison methods. Our investigations also reveal promising directions for further in-depth analyses of promiscuity and druggability in a pocket-centered manner. Drawbacks concerning binding site similarity assessment and druggability prediction are outlined, enabling researchers to avoid the typical pitfalls of binding site analyses.

Graphical abstract: Binding site characterization – similarity, promiscuity, and druggability

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Supplementary files

Article information


Submitted
19 Feb 2019
Accepted
31 May 2019
First published
06 Jun 2019

Med. Chem. Commun., 2019,10, 1145-1159
Article type
Research Article

Binding site characterization – similarity, promiscuity, and druggability

C. Ehrt, T. Brinkjost and O. Koch, Med. Chem. Commun., 2019, 10, 1145
DOI: 10.1039/C9MD00102F

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