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J Comput Aided Mol Des. 2002 Dec;16(12):935-53.

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

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Department of Biology and Biochemistry, University of Houston, Houston, TX 77204-5001, USA.


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

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