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

Area of Science:

• Biochemistry
• Enzymology
• Medicinal Chemistry

Background:

• CD38 is a key enzyme in calcium signaling, catalyzing the formation and metabolism of cyclic adenosine 5 ext2019-diphosphoribose (cADPR).
• Limited availability of CD38 inhibitors necessitates the development of novel therapeutic agents.
• Structure-based inhibitor design using non-hydrolyzable ligands is crucial for understanding enzyme-ligand interactions.

Purpose of the Study:

• To design and synthesize novel, potent inhibitors of CD38 enzyme activity.
• To elucidate the binding modes of novel inhibitors within the CD38 active site using X-ray crystallography.
• To identify key structural features for optimizing CD38 inhibition.

Main Methods:

• Molecular docking was employed to predict binding interactions of cyclic inosine 5 ext2019-diphosphoribose (N1-cIDPR) with CD38.
• Chemical modifications at the C-8 position of N1-cIDPR were synthesized and evaluated for inhibitory activity.
• X-ray crystallography was used to determine the structures of CD38 complexes with novel inhibitors.

Main Results:

• 8-amino N1-cIDPR demonstrated improved CD38 inhibition (IC50 56 µM) through interactions with Asp-155 and Glu-146.
• Cyclic ADP-carbocyclic ribose (cADPcR) showed potent inhibition (IC50 129 µM) via hydrogen bonding with Glu-146.
• A new series of N1-inosine 5 ext2019-monophosphates (N1-IMPs) exhibited potent CD38 inhibition, with the best compound showing an IC50 of 7.6 µM.

Conclusions:

• The N1-cIDPR and cADPcR structures reveal crucial binding interactions within the CD38 active site, particularly involving the ribose monophosphate region.
• The N1-IMPs represent a simplified and highly effective class of CD38 inhibitors.
• These findings provide a strong foundation for the development of novel therapeutics targeting CD38.