Discovery of a novel and potent class of F. tularensis enoyl-reductase (FabI) inhibitors by molecular shape and electrostatic matching

Kirk Hevener, Shahila Mehboob, Pin Chih Su, Kent Truong, Teuta Boci, Jiangping Deng, Mahmood Ghassemi, James L. Cook, Michael E. Johnson

Research output: Contribution to journalArticle

49 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)268-279
Number of pages12
JournalJournal of Medicinal Chemistry
Volume55
Issue number1
DOIs
StatePublished - Jan 12 2012
Externally publishedYes

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Static Electricity
Acyl Carrier Protein
Oxidoreductases
Enzymes
Francisella tularensis
Ligands
Structure-Activity Relationship
NAD
Libraries
Catalytic Domain
Fatty Acids
Anti-Bacterial Agents

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Discovery of a novel and potent class of F. tularensis enoyl-reductase (FabI) inhibitors by molecular shape and electrostatic matching. / Hevener, Kirk; Mehboob, Shahila; Su, Pin Chih; Truong, Kent; Boci, Teuta; Deng, Jiangping; Ghassemi, Mahmood; Cook, James L.; Johnson, Michael E.

In: Journal of Medicinal Chemistry, Vol. 55, No. 1, 12.01.2012, p. 268-279.

Research output: Contribution to journalArticle

Hevener, Kirk ; Mehboob, Shahila ; Su, Pin Chih ; Truong, Kent ; Boci, Teuta ; Deng, Jiangping ; Ghassemi, Mahmood ; Cook, James L. ; Johnson, Michael E. / Discovery of a novel and potent class of F. tularensis enoyl-reductase (FabI) inhibitors by molecular shape and electrostatic matching. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 1. pp. 268-279.
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