1xep

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'''Catechol in complex with T4 lysozyme L99A/M102Q'''<br />
'''Catechol in complex with T4 lysozyme L99A/M102Q'''<br />
==Overview==
==Overview==
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Molecular docking is widely used to predict novel lead compounds for drug, discovery. Success depends on the quality of the docking scoring function, among other factors. An imperfect scoring function can mislead by, predicting incorrect ligand geometries or by selecting nonbinding, molecules over true ligands. These false-positive hits may be considered, "decoys". Although these decoys are frustrating, they potentially provide, important tests for a docking algorithm; the more subtle the decoy, the, more rigorous the test. Indeed, decoy databases have been used to improve, protein structure prediction algorithms and protein-protein docking, algorithms. Here, we describe 20 geometric decoys in five enzymes and 166, "hit list" decoys-i.e., molecules predicted to bind by our docking program, that were tested and found not to do so-for beta-lactamase and two cavity, sites in lysozyme. Especially in the cavity sites, which are very simple, these decoys highlight particular weaknesses in our scoring function. We, also consider the performance of five other widely used docking scoring, functions against our geometric and hit list decoys. Intriguingly, whereas, many of these other scoring functions performed better on the geometric, decoys, they typically performed worse on the hit list decoys, often, highly ranking molecules that seemed to poorly complement the model sites., Several of these "hits"from the other scoring functions were tested, experimentally and found, in fact, to be decoys. Collectively, these, decoys provide a tool for the development and improvement of molecular, docking scoring functions. Such improvements may, in turn, be rapidly, tested experimentally against these and related experimental systems, which are well-behaved in assays and for structure determination.
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Molecular docking is widely used to predict novel lead compounds for drug discovery. Success depends on the quality of the docking scoring function, among other factors. An imperfect scoring function can mislead by predicting incorrect ligand geometries or by selecting nonbinding molecules over true ligands. These false-positive hits may be considered "decoys". Although these decoys are frustrating, they potentially provide important tests for a docking algorithm; the more subtle the decoy, the more rigorous the test. Indeed, decoy databases have been used to improve protein structure prediction algorithms and protein-protein docking algorithms. Here, we describe 20 geometric decoys in five enzymes and 166 "hit list" decoys-i.e., molecules predicted to bind by our docking program that were tested and found not to do so-for beta-lactamase and two cavity sites in lysozyme. Especially in the cavity sites, which are very simple, these decoys highlight particular weaknesses in our scoring function. We also consider the performance of five other widely used docking scoring functions against our geometric and hit list decoys. Intriguingly, whereas many of these other scoring functions performed better on the geometric decoys, they typically performed worse on the hit list decoys, often highly ranking molecules that seemed to poorly complement the model sites. Several of these "hits"from the other scoring functions were tested experimentally and found, in fact, to be decoys. Collectively, these decoys provide a tool for the development and improvement of molecular docking scoring functions. Such improvements may, in turn, be rapidly tested experimentally against these and related experimental systems, which are well-behaved in assays and for structure determination.
==About this Structure==
==About this Structure==
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1XEP is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bacteriophage_t4 Bacteriophage t4] with PO4, CAQ and BME as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Lysozyme Lysozyme], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.17 3.2.1.17] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1XEP OCA].
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1XEP is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bacteriophage_t4 Bacteriophage t4] with <scene name='pdbligand=PO4:'>PO4</scene>, <scene name='pdbligand=CAQ:'>CAQ</scene> and <scene name='pdbligand=BME:'>BME</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Lysozyme Lysozyme], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.17 3.2.1.17] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XEP OCA].
==Reference==
==Reference==
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[[Category: Single protein]]
[[Category: Single protein]]
[[Category: Brenk, R.]]
[[Category: Brenk, R.]]
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[[Category: Graves, A.P.]]
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[[Category: Graves, A P.]]
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[[Category: Shoichet, B.K.]]
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[[Category: Shoichet, B K.]]
[[Category: BME]]
[[Category: BME]]
[[Category: CAQ]]
[[Category: CAQ]]
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[[Category: glycosidase]]
[[Category: glycosidase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:54:01 2008''

Revision as of 13:54, 21 February 2008

Image:1xep.gif

1xep, resolution 1.55Å

Drag the structure with the mouse to rotate

Catechol in complex with T4 lysozyme L99A/M102Q

Overview

Molecular docking is widely used to predict novel lead compounds for drug discovery. Success depends on the quality of the docking scoring function, among other factors. An imperfect scoring function can mislead by predicting incorrect ligand geometries or by selecting nonbinding molecules over true ligands. These false-positive hits may be considered "decoys". Although these decoys are frustrating, they potentially provide important tests for a docking algorithm; the more subtle the decoy, the more rigorous the test. Indeed, decoy databases have been used to improve protein structure prediction algorithms and protein-protein docking algorithms. Here, we describe 20 geometric decoys in five enzymes and 166 "hit list" decoys-i.e., molecules predicted to bind by our docking program that were tested and found not to do so-for beta-lactamase and two cavity sites in lysozyme. Especially in the cavity sites, which are very simple, these decoys highlight particular weaknesses in our scoring function. We also consider the performance of five other widely used docking scoring functions against our geometric and hit list decoys. Intriguingly, whereas many of these other scoring functions performed better on the geometric decoys, they typically performed worse on the hit list decoys, often highly ranking molecules that seemed to poorly complement the model sites. Several of these "hits"from the other scoring functions were tested experimentally and found, in fact, to be decoys. Collectively, these decoys provide a tool for the development and improvement of molecular docking scoring functions. Such improvements may, in turn, be rapidly tested experimentally against these and related experimental systems, which are well-behaved in assays and for structure determination.

About this Structure

1XEP is a Single protein structure of sequence from Bacteriophage t4 with , and as ligands. Active as Lysozyme, with EC number 3.2.1.17 Full crystallographic information is available from OCA.

Reference

Decoys for docking., Graves AP, Brenk R, Shoichet BK, J Med Chem. 2005 Jun 2;48(11):3714-28. PMID:15916423

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