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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 ( N 1-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  N 1-cIDPR (IC 50  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  N 1-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 (IC 50  56 µM). Crystallography of a complex of cyclic ADP-carbocyclic ribose (cADPcR, IC 50  129 µM) with CD38 illustrated that Glu-146 hydrogen bonds with the ligand  N 6-amino group. Both 8-amino  N 1-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  N 1-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  N 1-inosine 5′-monophosphates ( N 1-IMPs). These small fragments inhibit hydrolysis of cADPR more efficiently than the parent cyclic compounds, with the best in the series demonstrating potent inhibition (IC 50  = 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.

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