Enoyl reductase, FabI, catalyzes a key step in bacterial fatty acid biosynthesis, and presents an attractive target for antimicrobial drug design.  Although published inhibitory compounds exist, there is a need to identify FabI inhibitors with novel chemical scaffolds and improved pharmacokinetic profiles.  Using a crystal structure of F. tularensis FabI solved in-house and the chemical structures of the known inhibitors, we have investigated three different virtual screening techniques.  A structure-based approach, Dynamic Pharmacophore Modeling, and two ligand-based approaches, Shape/Electrostatic Matching, and Common Pharmacophore Filtering, were employed to virtually screen two large chemical libraries numbering over 500,000 compounds. Several novel compounds with distinct chemical scaffolds and activity in the low micromolar range have been identified.  Herein we report the structures and activities of the compounds that were identified, discuss preliminary SAR and key binding features, and analyze the performance of the different virtual screening strategies.  Supported by NIH grant AI077949.

Identification of novel F. tularensis enoyl reductase (FabI) inhibitors by shape matching, common pharmacophore, and dynamic pharmacophore modeling

243rd National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.