Design, synthesis and biological characterization of novel inhibitors of CD38

Org Biomol Chem. 2011 May 7;9(9):3246-57. doi: 10.1039/c0ob00768d. Epub 2011 Mar 23.

Abstract

Human CD38 is a novel multi-functional protein that acts not only as an antigen for B-lymphocyte activation, but also as an enzyme catalyzing the synthesis of a Ca(2+) messenger molecule, cyclic ADP-ribose, from NAD(+). It is well established that this novel Ca(2+) signaling enzyme is responsible for regulating a wide range of physiological functions. Based on the crystal structure of the CD38/NAD(+) complex, we synthesized a series of simplified N-substituted nicotinamide derivatives (Compound 1-14). A number of these compounds exhibited moderate inhibition of the NAD(+) utilizing activity of CD38, with Compound 4 showing the highest potency. The crystal structure of CD38/Compound 4 complex and computer simulation of Compound 7 docking to CD38 show a significant role of the nicotinamide moiety and the distal aromatic group of the compounds for substrate recognition by the active site of CD38. Biologically, we showed that both Compounds 4 and 7 effectively relaxed the agonist-induced contraction of muscle preparations from rats and guinea pigs. This study is a rational design of inhibitors for CD38 that exhibit important physiological effects, and can serve as a model for future drug development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-ribosyl Cyclase 1 / antagonists & inhibitors*
  • ADP-ribosyl Cyclase 1 / chemical synthesis*
  • ADP-ribosyl Cyclase 1 / chemistry
  • Animals
  • Drug Design
  • Guinea Pigs
  • Male
  • Models, Molecular
  • Protein Interaction Domains and Motifs
  • Rats

Substances

  • ADP-ribosyl Cyclase 1