A structure-based design approach for the identification of novel inhibitors: application to an alanine racemase.

摘要: We report a new structure-based strategy for the identification of novel inhibitors. This approach has been applied to Bacillus stearothermophilus alanine racemase (AlaR), an enzyme implicated in biosynthesis bacterial cell wall. The catalyzes racemization L- and D-alanine using pyridoxal 5'-phosphate (PLP) as cofactor. restriction AlaR bacteria some fungi absolute requirement peptidoglycan make suitable target drug design. Unfortunately, known inhibitors are not specific inhibit activity other PLP-dependent enzymes, leading neurological side effects. article describes development receptor-based pharmacophore model AllaR, taking into account receptor flexibility (i.e. 'dynamic' model). In order accomplish this, molecular dynamics (MD) simulations were performed on full dimer from (PDB entry, 1 sft) with molecule one active site non-covalent inhibitor, propionate, second this homodimer. basic followed study was utilize conformations protein obtained during MD generate dynamic property mapping capability LigBuilder program. Compounds Available Chemicals Directory that fit identified have submitted experimental testing. described here can be used valuable tool design biomolecular targets.