How Significant Are Unusual Protein–Ligand Interactions? Insights from Database Mining

• Published in: Journal of medicinal chemistry Vol. 62; no. 22; pp. 10441 - 10455
• Main Authors: Kuhn, Bernd, Gilberg, Erik, Taylor, Robin, Cole, Jason, Korb, Oliver
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 27.11.2019
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b01545

We present a new approach to derive interaction propensities of protein–ligand atom pairs from mining of the Protein Data Bank. To ensure solid statistics, we use a line-of-sight contact filter and normalize the observed frequency of hits by a statistical null model based on exposed surface areas of atom types in the protein–ligand binding site. This allows us to investigate which intermolecular interactions and geometries are found more often than expected by chance in protein–ligand complexes. We focus our study on some of the unusual interactions that were postulated to be favorable, including σ-hole bonding of halogen and sulfur atoms, weak hydrogen bonding with fluorine as acceptor, and different types of dipolar interactions. Our results confirm some and challenge other common assumptions on these interactions and highlight other contact types that are yet underexplored in structure-based drug design.