Discovery of Antibacterial Biotin Carboxylase Inhibitors by Virtual Screening and Fragment-Based Approaches

Journal Article · Fri Jul 24 04:00:00 EDT 2009 · ACS Chem. Biol.

DOI:https://doi.org/10.1021/cb9000102· OSTI ID:1005751

Mochalkin, Igor; Miller, J Richard; Narasimhan, Lakshmi; Thanabal, Venkataraman; Erdman, Paul; Cox, Philip B; Prasad, J V.N. Vara; Lightle, Sandra; Huband, Michael D; Stover, C Kendall; Pfizer,

As part of our effort to inhibit bacterial fatty acid biosynthesis through the recently validated target biotin carboxylase, we employed a unique combination of two emergent lead discovery strategies. We used both de novo fragment-based drug discovery and virtual screening, which employs 3D shape and electrostatic property similarity searching. We screened a collection of unbiased low-molecular-weight molecules and identified a structurally diverse collection of weak-binding but ligand-efficient fragments as potential building blocks for biotin carboxylase ATP-competitive inhibitors. Through iterative cycles of structure-based drug design relying on successive fragment costructures, we improved the potency of the initial hits by up to 3000-fold while maintaining their ligand-efficiency and desirable physicochemical properties. In one example, hit-expansion efforts resulted in a series of amino-oxazoles with antibacterial activity. These results successfully demonstrate that virtual screening approaches can substantially augment fragment-based screening approaches to identify novel antibacterial agents.

• Research Organization: Argonne National Laboratory (ANL)
• Sponsoring Organization: USDOE
• OSTI ID: 1005751
• Journal Information: ACS Chem. Biol., Journal Name: ACS Chem. Biol. Journal Issue: (6) ; 06, 2009 Vol. 4
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
99 GENERAL AND MISCELLANEOUS
BIOSYNTHESIS
BIOTIN
CARBOXYLASE
CARBOXYLIC ACIDS
DESIGN
ELECTROSTATICS
SHAPE
TARGETS