Alanine racemase: A structural model for drug design

Alanine Racemase (AlaR) is the first enzyme in the biosynthetic pathway of the peptidoglycan synthesis catalyzing the racemization of L- and D-alanine by using pyridoxal 5′-phosphate (PLP) as a cofactor. The fact that all of the known bacteria require D-alanine, while only L-alanine is used in eukaryotic protein synthesis, makes AlaR a suitable target for drug design.; A number of known AlaR inhibitors are of particular interest as agents against Mycobacterium tuberculosis. However, most of these compounds are suicide inhibitors that react with the cofactor itself, inhibiting the activity of many PLP containing enzymes due to their lack of target specificity.; A molecular dynamics simulation was performed on the Bacillus stearothermophilus AlaR homodimer in order to understand the structural determinants for the binding of the substrate/inhibitor. The results described herein constitute the framework for the subsequent steps of structure-based design intended to help in the identification of novel inhibitors.