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) Cofactor

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• 作者：Ilenia Giangreco ; Martin J. Packer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：August 8, 2013
• 年：2013
• 卷：56
• 期：15
• 页码：6175-6189
• 全文大小：727K
• 年卷期：v.56,no.15(August 8, 2013)
• ISSN：1520-4804

文摘

We have analyzed the protein-binding pharmacophore of NAD and its close analogues in all protein鈥搇igand 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鈥搇igand structures containing NAD analogues; we have benchmarked this set of contacts against nearly 27鈥?00 protein鈥搇igand 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.