2pu4: Difference between revisions

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[[Image:2pu4.jpg|left|200px]]
{{Seed}}
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{{STRUCTURE_2pu4|  PDB=2pu4  |  SCENE=  }}  
{{STRUCTURE_2pu4|  PDB=2pu4  |  SCENE=  }}  


'''AmpC beta-lacamase with bound covalent oxadiazole inhibitor'''
===AmpC beta-lacamase with bound covalent oxadiazole inhibitor===




==Overview==
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High-throughput screening (HTS) is widely used in drug discovery. Especially for screens of unbiased libraries, false positives can dominate "hit lists"; their origins are much debated. Here we determine the mechanism of every active hit from a screen of 70,563 unbiased molecules against beta-lactamase using quantitative HTS (qHTS). Of the 1274 initial inhibitors, 95% were detergent-sensitive and were classified as aggregators. Among the 70 remaining were 25 potent, covalent-acting beta-lactams. Mass spectra, counter-screens, and crystallography identified 12 as promiscuous covalent inhibitors. The remaining 33 were either aggregators or irreproducible. No specific reversible inhibitors were found. We turned to molecular docking to prioritize molecules from the same library for testing at higher concentrations. Of 16 tested, 2 were modest inhibitors. Subsequent X-ray structures corresponded to the docking prediction. Analog synthesis improved affinity to 8 microM. These results suggest that it may be the physical behavior of organic molecules, not their reactivity, that accounts for most screening artifacts. Structure-based methods may prioritize weak-but-novel chemotypes in unbiased library screens.
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==About this Structure==
==About this Structure==
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[[Category: Ampc beta-lactamase oxadiazole]]
[[Category: Ampc beta-lactamase oxadiazole]]
[[Category: Hydrolase]]
[[Category: Hydrolase]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Apr 16 23:04:28 2008''
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 04:26:45 2008''

Revision as of 01:26, 29 July 2008

File:2pu4.png

Template:STRUCTURE 2pu4

AmpC beta-lacamase with bound covalent oxadiazole inhibitor

Template:ABSTRACT PUBMED 18333608

About this Structure

2PU4 is a Single protein structure of sequence from Escherichia coli. Full crystallographic information is available from OCA.

Reference

Comprehensive Mechanistic Analysis of Hits from High-Throughput and Docking Screens against beta-Lactamase., Babaoglu K, Simeonov A, Irwin JJ, Nelson ME, Feng B, Thomas CJ, Cancian L, Costi MP, Maltby DA, Jadhav A, Inglese J, Austin CP, Shoichet BK, J Med Chem. 2008 Mar 12;. PMID:18333608

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