Inhibitors of dihydrodipicolinate reductase, a key enzyme of the diaminopimelate pathway of Mycobacterium tuberculosis

Anthony M. Paiva, Dana E. Vanderwall, John S. Blanchard, John W. Kozarich, Joanne M. Williamson, Theresa M. Kelly

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

Tuberculosis (TB) remains a leading cause of infectious disease in the world today and therapies developed over the last forty years are becoming increasingly ineffective against resistant strains of Mycobacterium tuberculosis. In an effort to explore new mechanisms for drug development, we have investigated the enzymes of the diaminopimelate biosynthetic pathway as potential targets. Specifically, dihydrodipicolinate reductase, the essential gene product of dapB, was screened for novel inhibitors. Inhibitors were identified both by a molecular modeling approach which utilized the available crystal structure of the enzyme with an inhibitor bound at the active site as well as by more conventional screening strategies. The resulting compounds contain a number of structural motifs and were all found to be competitive with respect to the DHDP substrate. The Ki values for the inhibitors range from 10 to 90 μM. The molecular modeling approach was very effective in identifying novel inhibitors of the enzyme. These compounds were obtained at a higher frequency based on the number of compounds analyzed than those inhibitors discovered via conventional screening. However, conventional screening proved beneficial in identifying compounds with greater structural diversity.

Original languageEnglish (US)
Pages (from-to)67-77
Number of pages11
JournalBiochimica et Biophysica Acta - Protein Structure and Molecular Enzymology
Volume1545
Issue number1-2
DOIs
Publication statusPublished - Feb 9 2001

    Fingerprint

Keywords

  • (Mycobacterium tuberculosis)
  • Diaminopimelate
  • Dihydrodipicolinate
  • Enzyme inhibitor
  • Molecular modeling

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology

Cite this