title: CD38 Structure-Based Inhibitor Design Using the N1-Cyclic Inosine 5'-Diphosphate Ribose Template.
abstract: 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.
authors.affiliation: Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom.
authors.forename: Christelle
authors.initials: C
authors.lastname: Moreau
authors.forename: Qun
authors.initials: Q
authors.lastname: Liu
authors.forename: Richard
authors.initials: R
authors.lastname: Graeff
authors.forename: Gerd K
authors.initials: GK
authors.lastname: Wagner
authors.forename: Mark P
authors.initials: MP
authors.lastname: Thomas
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Swarbrick
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
authors.forename: Hon Cheung
authors.initials: HC
authors.lastname: Lee
authors.forename: Quan
authors.initials: Q
authors.lastname: Hao
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives* / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006860:Hydrogen Bonding; D007290:Inosine Diphosphate; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008970:Molecular Weight; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; C439996:cyclic ADP-carbocyclic-ribose; D036563:Cyclic ADP-Ribose; D007290:Inosine Diphosphate; D051997:ADP-ribosyl Cyclase 1