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

TitleCD38 Structure-Based Inhibitor Design Using the N1-Cyclic Inosine 5′-Diphosphate Ribose Template
Authors
Issue Date2013
Citation
PLoS ONE, 2013, v. 8, p. e66247 How to Cite?
AbstractFew inhibitors exist for CD38, a multifunctional enzyme catalyzing the formation and metabolism of the Ca2+-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.
Persistent Identifierhttp://hdl.handle.net/10722/184662
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorMoreau, Cen_US
dc.contributor.authorLiu, Qen_US
dc.contributor.authorGraeff, RMen_US
dc.contributor.authorWagner, GKen_US
dc.contributor.authorThomas, MPen_US
dc.contributor.authorSwarbrick, JMen_US
dc.contributor.authorShuto, Sen_US
dc.contributor.authorLee, HCen_US
dc.contributor.authorHao, Qen_US
dc.contributor.authorPotter, BVLen_US
dc.date.accessioned2013-07-15T10:02:31Z-
dc.date.available2013-07-15T10:02:31Z-
dc.date.issued2013en_US
dc.identifier.citationPLoS ONE, 2013, v. 8, p. e66247en_US
dc.identifier.urihttp://hdl.handle.net/10722/184662-
dc.description.abstractFew inhibitors exist for CD38, a multifunctional enzyme catalyzing the formation and metabolism of the Ca2+-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.-
dc.languageengen_US
dc.relation.ispartofPLoS ONEen_US
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.titleCD38 Structure-Based Inhibitor Design Using the N1-Cyclic Inosine 5′-Diphosphate Ribose Templateen_US
dc.typeArticleen_US
dc.identifier.emailGraeff, RM: graeffr@hku.hken_US
dc.identifier.emailLee, HC: leehc@hku.hken_US
dc.identifier.emailHao, Q: qhao@hku.hken_US
dc.identifier.authorityGraeff, RM=rp01464en_US
dc.identifier.authorityLee, HC=rp00545en_US
dc.identifier.authorityHao, Q=rp01332en_US
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.pone.0066247-
dc.identifier.pmcidPMC3686795-
dc.identifier.hkuros215981en_US
dc.identifier.volume8en_US
dc.identifier.spagee66247en_US
dc.identifier.epagee66247en_US

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