2W6O

Crystal structure of Biotin carboxylase from E. coli in complex with 4-Amino-7,7-dimethyl-7,8-dihydro-quinazolinone fragment

Summary for 2W6O

• Entry DOI: 10.2210/pdb2w6o/pdb
• Related: 1BNC 1DV1 1DV2 1K69 2GPS 2GPW 2J9G 2V58 2V59 2V5A 2VR1 2W6M 2W6N 2W6P 2W6Q 2W6Z 2W70 2W71 2W7C
• Descriptor: BIOTIN CARBOXYLASE, 4-amino-7,7-dimethyl-7,8-dihydroquinazolin-5(6H)-one, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: ligase, atp-binding, fatty acid biosynthesis, nucleotide-binding, lipid synthesis, atp-grasp domain, fragment screening
• Biological source: ESCHERICHIA COLI
• Total number of polymer chains: 2
• Total formula weight: 99226.68

Authors

Mochalkin, I.,Miller, J.R. (deposition date: 2008-12-18, release date: 2009-05-19, Last modification date: 2023-12-13)

Primary citation

Mochalkin, I.,Miller, J.R.,Narasimhan, L.S.,Thanabal, V.,Erdman, P.,Cox, P.,Prasad, J.V.,Lightle, S.,Huband, M.,Stover, K.
Discovery of Antibacterial Biotin Carboxylase Inhibitors by Virtual Screening and Fragment-Based Approaches.
Acs Chem.Biol., 4:473-, 2009

PubMed Abstract: 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.

PubMed: 19413326
DOI: 10.1021/CB9000102

Experimental method

X-RAY DIFFRACTION (2.5 Å)