Pharmacophore binding motifs for nicotinamide adenine dinucleotide analogues across multiple protein families: a detailed contact-based analysis of the interaction between proteins and NAD(P) cofactors.

We have analyzed the protein-binding pharmacophore of NAD and its close analogues in all protein–ligand structures available in the RCSB database as of February 2012; this analysis has then been used to assess the novelty of structures emerging after that date. We show that proteins have evolved diverse pharmacophore motifs for binding the adenine moiety, fewer, but still diverse, motifs for nicotinamide, and a very limited set of motifs for binding the pyrophosphate linker. Our exhaustive analysis includes a pharmacophore contact analysis for over 1900 protein–ligand structures containing NAD analogues; we have benchmarked this set of contacts against nearly 27 000 protein–ligand structures to demonstrate that the diversity of interactions seen with NAD is very similar to that seen for all other ligands. Hence, variation in binding motifs for NAD is not distinct from that observed for other ligands and they show significant variation across protein families.