Discovery of Enoyl-Reductase (FabI) Inhibitors by Molecular Shape and Electrostatic Matching.

Hevener KE, Mehboob S, Su PC, Truong K, Boci T, Deng J, Ghassemi M, Cook JL, Johnson ME. "J Med Chem. 2011 Dec"
Enoyl-acyl carrier protein (ACP) reductase, FabI, is really a key enzyme in the bacterial fatty acid biosynthesis pathway (FAS II). FabI is definitely an NADH-dependent oxidoreductase that functions to cut down enoyl-ACP substrates inside a last stage of the pathway. The absence of this enzyme in humans tends to make it an attractive target for the development of new antibacterial agents.

FabI is known to be unresponsive to structure-based design efforts resulting from a high diploma of induced fit plus a cell versatile loop encompassing the energetic web page.

Here we discuss the improvement, validation, and careful app of a ligand-based virtual display used for your identification of novel inhibitors in the Francisella tularensis FabI focus on.

In this research, 4 known courses of FabI inhibitors had been utilised as templates for virtual screens that concerned molecular form and electrostatic matching. The plan ROCS was made use of to go looking a high throughput screening library for compounds that matched any with the four molecular form queries. Matching compounds were additional refined applying the system EON, which compares and scores compounds by matching electrostatic homes. Employing these approaches, fifty compounds had been chosen, ordered, and examined.

The examined compounds possessed novel chemical scaffolds when compared to the input question compounds. Numerous hits with low micromolar exercise were discovered and follow-up scaffold-based searches resulted within the identification of the lead sequence with submicromolar enzyme inhibition, high ligand efficiency, and also a novel scaffold.

Additionally, just about the most active compounds showed promising whole-cell antibacterial activity from various Gram-positive and Gram-negative species, such as the goal pathogen.