CD38 Structure-Based Inhibitor Design Using the N1-Cyclic Inosine 5'-Diphosphate Ribose Template

• Published in: PloS one 2013-06, Vol.8 (6), p.e66247-e66247
• Main Authors: Moreau, Christelle, Liu, Qun, Graeff, Richard, Wagner, Gerd K, Thomas, Mark P, Swarbrick, Joanna M, Shuto, Satoshi, Lee, Hon Cheung, Hao, Quan, Potter, Barry V L
• Format: Article
• Language: English
• Subjects: Adenosine; Adenosine diphosphate; ADP-ribosyl Cyclase 1 - antagonists & inhibitors; ADP-ribosyl Cyclase 1 - chemistry; Aplysia californica; Biology; Calcium metabolism; Calcium mobilization; Catalysis; Catalytic Domain; CD38 antigen; Chemical bonds; Chemistry; Computer Science; Crystallography; Crystallography, X-Ray; Cyclic ADP-ribose; Cyclic ADP-Ribose - analogs & derivatives; Cyclic ADP-Ribose - chemistry; Cyclic compounds; Design; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Genetic algorithms; Hydrogen; Hydrogen Bonding; Hydrogen bonds; Hydrogen ion concentration; Hydrolysis; Inhibition; Inhibitors; Inosine Diphosphate; Laboratories; Ligands; Metabolism; Mimicry; Models, Molecular; Molecular docking; Molecular Docking Simulation; Molecular structure; Molecular Weight; Monosaccharides; Pharmaceutical sciences; Pharmacology; Pharmacy; Physiological aspects; Physiology; Protein Binding; Proteins; Ribose; Structure-Activity Relationship
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0066247

Few inhibitors exist for CD38, a multifunctional enzyme catalyzing the formation and metabolism of the Ca(2+)-mobilizing second messenger cyclic adenosine 5'-diphosphoribose (cADPR). Synthetic, non-hydrolyzable ligands can facilitate structure-based inhibitor design. Molecular docking was used to reproduce the crystallographic binding mode of cyclic inosine 5'-diphosphoribose (N1-cIDPR) with CD38, revealing an exploitable pocket and predicting the potential to introduce an extra hydrogen bond interaction with Asp-155. The purine C-8 position of N1-cIDPR (IC50 276 µM) was extended with an amino or diaminobutane group and the 8-modified compounds were evaluated against CD38-catalyzed cADPR hydrolysis. Crystallography of an 8-amino N1-cIDPR:CD38 complex confirmed the predicted interaction with Asp-155, together with a second H-bond from a realigned Glu-146, rationalizing the improved inhibition (IC50 56 µM). Crystallography of a complex of cyclic ADP-carbocyclic ribose (cADPcR, IC50 129 µM) with CD38 illustrated that Glu-146 hydrogen bonds with the ligand N6-amino group. Both 8-amino N1-cIDPR and cADPcR bind deep in the active site reaching the catalytic residue Glu-226, and mimicking the likely location of cADPR during catalysis. Substantial overlap of the N1-cIDPR "northern" ribose monophosphate and the cADPcR carbocyclic ribose monophosphate regions suggests that this area is crucial for inhibitor design, leading to a new compound series of N1-inosine 5'-monophosphates (N1-IMPs). These small fragments inhibit hydrolysis of cADPR more efficiently than the parent cyclic compounds, with the best in the series demonstrating potent inhibition (IC50 = 7.6 µM). The lower molecular weight and relative simplicity of these compounds compared to cADPR make them attractive as a starting point for further inhibitor design.