Inhibitors of dihydrodipicolinate reductase, a key enzyme of the diaminopimelate pathway of Mycobacterium tuberculosis.
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 K(i) values for the inhibitors range from 10 to 90 microM. 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.
Paiva
A M
AM
Department of Endocrinology and Chemical Biology, Merck Research Laboratories, Rahway, NJ 07065, USA.
Vanderwall
D E
DE
Blanchard
J S
JS
Kozarich
J W
JW
Williamson
J M
JM
Kelly
T M
TM
D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001665:Binding Sites / Q000187:drug effects; D003960:Diaminopimelic Acid / Q000378:metabolism; D050746:Dihydrodipicolinate Reductase; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011487:Protein Conformation; D013449:Sulfonamides / Q000494:pharmacology
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D003960:Diaminopimelic Acid; D010088:Oxidoreductases; D050746:Dihydrodipicolinate Reductase; D044925:Oxidoreductases Acting on CH-CH Group Donors