Crystal structure of Rattus norvegicus Visfatin/PBEF/Nampt in complex with an FK866-based inhibitor

Mol Cells. 2009 Jun 30;27(6):667-71. doi: 10.1007/s10059-009-0088-x. Epub 2009 Jun 12.

Abstract

Visfatin (Nampt/PBEF) plays a pivotal role in the salvage pathway for NAD(+) biosynthesis. Its potent inhibitor, FK866, causes cellular NAD(+) levels to decline, thereby inducing apoptosis in tumor cells. In an effort to improve the solubility and binding interactions of FK866, we designed and synthesized IS001, in which a ribose group is attached to the FK866 pyridyl ring. Here, we report the crystal structure of rat visfatin in complex with IS001. Like FK866, IS001 is positioned at the dimer interface, and all of the residues that interact with IS001 are involved in hydrophobic or pi-pi-stacking interactions. However, we were unable to detect any strong interactions between the added ribose ring of IS001 and visfatin, which implies that a bulkier modifying group is necessary for a tight interaction. This study provides additional structure-based information needed to optimize the design of visfatin inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylamides / chemistry*
  • Acrylamides / pharmacology*
  • Animals
  • Binding Sites
  • Calorimetry
  • Crystallography, X-Ray
  • Models, Molecular
  • Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors*
  • Nicotinamide Phosphoribosyltransferase / chemistry*
  • Piperidines / chemistry*
  • Piperidines / pharmacology*
  • Protein Multimerization
  • Protein Structure, Secondary
  • Pyridinium Compounds / chemistry*
  • Pyridinium Compounds / pharmacology*
  • Rats

Substances

  • Acrylamides
  • IS 001
  • N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
  • Piperidines
  • Pyridinium Compounds
  • Nicotinamide Phosphoribosyltransferase