2w6q | pdb_00002w6q
CRYSTAL STRUCTURE OF BIOTIN CARBOXYLASE FROM E. COLI IN COMPLEX WITH THE TRIAZINE-2,4-DIAMINE FRAGMENT
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedOne explanation for the lack of novel synthetic antibacterials emerging from target-based screening is that antibacterial target space and the physicochemical properties of antibacterials are significantly different from compounds comprising eukaryotic-biased pharmaceutical screening libraries. Efforts to derive new antibacterial drugs from natural products are hampered because complex natural products do not possess desirable drug-like properties and are less tractable for medicinal chemistry. Therefore, 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; a rapid, resource efficient route to generate novel ligand-efficient hits and virtual screening; which employs 3D shape and electrostatic property similarity searching leveraged from existing co-crystal structures. We screened a collection of unbiased low-molecular weight molecules and identified a structurally diverse collection of weak binding but ligand-efficient molecular fragments as potential drug-like building blocks for biotin carboxylase ATP-competitive inhibitors. Through iterative cycles of structure-based drug design relying on successive fragment co-structures, 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 attributed to BC inhibition. These results successfully demonstrate that virtual screening approaches can substantially augment fragment-based screening approaches to identify novel antibacterial agents, offering an alternative strategy for antibacterial discovery particularly applicable when intimate structural knowledge of target active sites and inhibitor binding modes is available. Discovery of Antibacterial Biotin Carboxylase Inhibitors by Virtual Screening and Fragment-Based Approaches.,Mochalkin I, Miller JR, Narasimhan LS, Thanabal V, Erdman P, Cox P, Prasad JV, Lightle S, Huband M, Stover K ACS Chem Biol. 2009 May 4. PMID:19413326[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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