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 worl d today and therapies developed over the last forty years are becoming incr easingly ineffective against resistant strains of Mycobacterium tuberculosi s. In an effort to explore new mechanisms for drug development, we have inv estigated the enzymes of the diaminopimelate biosynthetic pathway as potent ial targets. Specifically, dihydrodipicolinate reductase, the essential gen e product of dapB, was screened for novel inhibitors. Inhibitors were ident ified both by a molecular modeling approach which utilized the available cr ystal 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 rang e from 10 to 90 muM. The molecular modeling approach was very effective in identifying novel inhibitors of the enzyme. These compounds were obtained a t a higher frequency based on the number of compounds analyzed than those i nhibitors discovered via conventional screening. However, conventional scre ening proved beneficial in identifying compounds with greater structural di versity. (C) 2001 Elsevier Science B.V. All rights reserved.