Augmenting Structure-Based Design with Experimental Protein-Ligand Interaction Data: Molecular Recognition, Interactive Visualization, and Rescoring.

The previously introduced ratio of frequencies (R ) framework provides statistically sound information on the relative interaction preferences of atoms in crystal structures. By applying the methodology to protein-ligand complexes, we can investigate the significance of interactions that are employed in structure-based drug design. Here, we revisit three aspects of molecular recognition in the light of the R framework, namely stacking interactions of heteroaromatic rings with protein amide groups, interactions of acidified C-H groups, and interaction differences between syn and anti lone pairs of carboxylate groups. In addition, we introduce a highly interactive visualization tool that facilitates design idea generation in structure-enabled drug discovery projects. Finally, we show that applying the R analysis as a simple rescoring tool after docking improves enrichment factors for the DUD-E diverse targets subset supporting the relevance of our approach.