2W6P: Crystal Structure Of Biotin Carboxylase From E. Coli In Complex With 5-Methyl-6-Phenyl-Quinazoline-2,4-Diamine

Citation:
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.
PDB ID: 2W6PDownload
MMDB ID: 72703
PDB Deposition Date: 2008/12/18
Updated in MMDB: 2011/10
Experimental Method:
x-ray diffraction
Resolution: 1.85  Å
Source Organism:
Similar Structures:
Biological Unit for 2W6P: monomeric; determined by software (PISA)
Molecular Components in 2W6P
Label Count Molecule
Protein (1 molecule)
1
Acetyl-coa Carboxylase(Gene symbol: accC)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
.