title: Discovery of a novel and potent class of F. tularensis enoyl-reductase (FabI) inhibitors by molecular shape and electrostatic matching.
abstract: Enoyl-acyl carrier protein (ACP) reductase, FabI, is a key enzyme in the bacterial fatty acid biosynthesis pathway (FAS II). FabI is an NADH-dependent oxidoreductase that acts to reduce enoyl-ACP substrates in a final step of the pathway. The absence of this enzyme in humans makes it an attractive target for the development of new antibacterial agents. FabI is known to be unresponsive to structure-based design efforts due to a high degree of induced fit and a mobile flexible loop encompassing the active site. Here we discuss the development, validation, and careful application of a ligand-based virtual screen used for the identification of novel inhibitors of the  Francisella tularensis  FabI target. In this study, four known classes of FabI inhibitors were used as templates for virtual screens that involved molecular shape and electrostatic matching. The program ROCS was used to search a high-throughput screening library for compounds that matched any of the four molecular shape queries. Matching compounds were further refined using the program EON, which compares and scores compounds by matching electrostatic properties. Using these techniques, 50 compounds were selected, ordered, and tested. The tested compounds possessed novel chemical scaffolds when compared to the input query compounds. Several hits with low micromolar activity were identified and follow-up scaffold-based searches resulted in the identification of a lead series with submicromolar enzyme inhibition, high ligand efficiency, and a novel scaffold. Additionally, one of the most active compounds showed promising whole-cell antibacterial activity against several Gram-positive and Gram-negative species, including the target pathogen. The results of a preliminary structure-activity relationship analysis are presented.
authors.affiliation: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, Illinois 60607-7173, United States.
authors.forename: Kirk E
authors.initials: KE
authors.lastname: Hevener
authors.forename: Shahila
authors.initials: S
authors.lastname: Mehboob
authors.forename: Pin-Chih
authors.initials: PC
authors.lastname: Su
authors.forename: Kent
authors.initials: K
authors.lastname: Truong
authors.forename: Teuta
authors.initials: T
authors.lastname: Boci
authors.forename: Jiangping
authors.initials: J
authors.lastname: Deng
authors.forename: Mahmood
authors.initials: M
authors.lastname: Ghassemi
authors.forename: James L
authors.initials: JL
authors.lastname: Cook
authors.forename: Michael E
authors.initials: ME
authors.lastname: Johnson
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016208:Databases, Factual; D050745:Enoyl-(Acyl-Carrier Protein) Reductase (NADPH, B-Specific) / Q000037:antagonists & inhibitors*; D005604:Francisella tularensis / Q000187:drug effects / Q000201:enzymology*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D055672:Static Electricity; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D001593:Benzyl Compounds; D050745:Enoyl-(Acyl-Carrier Protein) Reductase (NADPH, B-Specific)
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