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PDBsum entry 2pu2
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* Residue conservation analysis
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J Med Chem
51:2502-2511
(2008)
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PubMed id:
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Comprehensive mechanistic analysis of hits from high-throughput and docking screens against beta-lactamase.
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K.Babaoglu,
A.Simeonov,
J.J.Irwin,
M.E.Nelson,
B.Feng,
C.J.Thomas,
L.Cancian,
M.P.Costi,
D.A.Maltby,
A.Jadhav,
J.Inglese,
C.P.Austin,
B.K.Shoichet.
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ABSTRACT
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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 1,274 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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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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C.Bebrone,
P.Lassaux,
L.Vercheval,
J.S.Sohier,
A.Jehaes,
E.Sauvage,
and
M.Galleni
(2010).
Current challenges in antimicrobial chemotherapy: focus on ß-lactamase inhibition.
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Drugs,
70,
651-679.
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J.Carlsson,
L.Yoo,
Z.G.Gao,
J.J.Irwin,
B.K.Shoichet,
and
K.A.Jacobson
(2010).
Structure-based discovery of A2A adenosine receptor ligands.
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J Med Chem,
53,
3748-3755.
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K.J.Simmons,
I.Chopra,
and
C.W.Fishwick
(2010).
Structure-based discovery of antibacterial drugs.
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Nat Rev Microbiol,
8,
501-510.
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L.B.Akella,
and
D.DeCaprio
(2010).
Cheminformatics approaches to analyze diversity in compound screening libraries.
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Curr Opin Chem Biol,
14,
325-330.
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N.Brooijmans,
and
C.Humblet
(2010).
Chemical space sampling by different scoring functions and crystal structures.
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J Comput Aided Mol Des,
24,
433-447.
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R.S.Ferreira,
A.Simeonov,
A.Jadhav,
O.Eidam,
B.T.Mott,
M.J.Keiser,
J.H.McKerrow,
D.J.Maloney,
J.J.Irwin,
and
B.K.Shoichet
(2010).
Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors.
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J Med Chem,
53,
4891-4905.
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PDB code:
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T.Tomasić,
N.Zidar,
A.Kovac,
S.Turk,
M.Simcic,
D.Blanot,
M.Müller-Premru,
M.Filipic,
S.G.Grdadolnik,
A.Zega,
M.Anderluh,
S.Gobec,
D.Kikelj,
and
L.Peterlin Masic
(2010).
5-Benzylidenethiazolidin-4-ones as multitarget inhibitors of bacterial Mur ligases.
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ChemMedChem,
5,
286-295.
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C.J.Thomas,
D.S.Auld,
R.Huang,
W.Huang,
A.Jadhav,
R.L.Johnson,
W.Leister,
D.J.Maloney,
J.J.Marugan,
S.Michael,
A.Simeonov,
N.Southall,
M.Xia,
W.Zheng,
J.Inglese,
and
C.P.Austin
(2009).
The pilot phase of the NIH Chemical Genomics Center.
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Curr Top Med Chem,
9,
1181-1193.
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D.G.Teotico,
K.Babaoglu,
G.J.Rocklin,
R.S.Ferreira,
A.M.Giannetti,
and
B.K.Shoichet
(2009).
Docking for fragment inhibitors of AmpC beta-lactamase.
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Proc Natl Acad Sci U S A,
106,
7455-7460.
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PDB codes:
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D.L.Mobley,
and
K.A.Dill
(2009).
Binding of small-molecule ligands to proteins: "what you see" is not always "what you get".
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Structure,
17,
489-498.
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D.M.Huryn,
and
A.B.Smith
(2009).
The identification, characterization and optimization of small molecule probes of cysteine proteases: experiences of the Penn Center for Molecular Discovery with cathepsin B and cathepsin L.
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Curr Top Med Chem,
9,
1206-1216.
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J.J.Irwin,
B.K.Shoichet,
M.M.Mysinger,
N.Huang,
F.Colizzi,
P.Wassam,
and
Y.Cao
(2009).
Automated docking screens: a feasibility study.
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J Med Chem,
52,
5712-5720.
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M.Xia,
K.Bi,
R.Huang,
M.H.Cho,
S.Sakamuru,
S.C.Miller,
H.Li,
Y.Sun,
J.Printen,
C.P.Austin,
and
J.Inglese
(2009).
Identification of small molecule compounds that inhibit the HIF-1 signaling pathway.
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Mol Cancer,
8,
117.
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T.Schwede,
A.Sali,
B.Honig,
M.Levitt,
H.M.Berman,
D.Jones,
S.E.Brenner,
S.K.Burley,
R.Das,
N.V.Dokholyan,
R.L.Dunbrack,
K.Fidelis,
A.Fiser,
A.Godzik,
Y.J.Huang,
C.Humblet,
M.P.Jacobson,
A.Joachimiak,
S.R.Krystek,
T.Kortemme,
A.Kryshtafovych,
G.T.Montelione,
J.Moult,
D.Murray,
R.Sanchez,
T.R.Sosnick,
D.M.Standley,
T.Stouch,
S.Vajda,
M.Vasquez,
J.D.Westbrook,
and
I.A.Wilson
(2009).
Outcome of a workshop on applications of protein models in biomedical research.
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Structure,
17,
151-159.
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Y.Chen,
and
B.K.Shoichet
(2009).
Molecular docking and ligand specificity in fragment-based inhibitor discovery.
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Nat Chem Biol,
5,
358-364.
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PDB codes:
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C.D.Snow
(2008).
Hunting for predictive computational drug-discovery models.
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Expert Rev Anti Infect Ther,
6,
291-293.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
