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Tautomer Preference in PDB Complexes and its Impact on Structure-Based Drug Discovery.

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Title: Tautomer Preference in PDB Complexes and its Impact on Structure-Based Drug Discovery.
Authors: Francesca Milletti1, Anna Vulpetti1
Source: Journal of Chemical Information & Modeling. Jun2010, Vol. 50 Issue 6, p1062-1074. 13p.
Subjects: Tautomerism, Drug development, Virtual reality, Binding sites, Protein structure, Molecular dynamics
Abstract: Tautomer enrichment is a key step of ligand preparation prior to virtual screening. In this paper, we have investigated how tautomer preference in various media (water, gas phase, and crystal) compares to tautomer preference at the active site of the protein by analyzing the different possible H-bonding contacts for a set of 13 tautomeric structures. In addition, we have explored the impact of four different protocols for the enumeration of tautomers in virtual screening by using Flap, Glide, and Gold as docking tools on seven targets of the DUD data set. Excluding targets in which the binding does not involve tautomeric atoms (HSP90, p38, and VEGFR2), we found that the average receiver operating characteristic curve enrichment at 10% was 0.25 (Gold), 0.24 (Glide), and 0.50 (Flap) by considering only tautomers predicted to be unstable in water versus 0.41 (Gold), 0.56 (Glide), 0.51 (Flap) by limiting the enumeration process only to the predicted most stable tautomer. The inclusion of all tautomers (stable and unstable) yielded slightly poorer results than considering only the most stable form in water. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Chemical Information & Modeling is the property of American Chemical Society and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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PubType: Academic Journal
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  Data: Tautomer Preference in PDB Complexes and its Impact on Structure-Based Drug Discovery.
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  Data: <searchLink fieldCode="AR" term="%22Francesca+Milletti%22">Francesca Milletti</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Anna+Vulpetti%22">Anna Vulpetti</searchLink><relatesTo>1</relatesTo>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Chemical+Information+%26+Modeling%22">Journal of Chemical Information & Modeling</searchLink>. Jun2010, Vol. 50 Issue 6, p1062-1074. 13p.
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  Data: <searchLink fieldCode="DE" term="%22Tautomerism%22">Tautomerism</searchLink><br /><searchLink fieldCode="DE" term="%22Drug+development%22">Drug development</searchLink><br /><searchLink fieldCode="DE" term="%22Virtual+reality%22">Virtual reality</searchLink><br /><searchLink fieldCode="DE" term="%22Binding+sites%22">Binding sites</searchLink><br /><searchLink fieldCode="DE" term="%22Protein+structure%22">Protein structure</searchLink><br /><searchLink fieldCode="DE" term="%22Molecular+dynamics%22">Molecular dynamics</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Tautomer enrichment is a key step of ligand preparation prior to virtual screening. In this paper, we have investigated how tautomer preference in various media (water, gas phase, and crystal) compares to tautomer preference at the active site of the protein by analyzing the different possible H-bonding contacts for a set of 13 tautomeric structures. In addition, we have explored the impact of four different protocols for the enumeration of tautomers in virtual screening by using Flap, Glide, and Gold as docking tools on seven targets of the DUD data set. Excluding targets in which the binding does not involve tautomeric atoms (HSP90, p38, and VEGFR2), we found that the average receiver operating characteristic curve enrichment at 10% was 0.25 (Gold), 0.24 (Glide), and 0.50 (Flap) by considering only tautomers predicted to be unstable in water versus 0.41 (Gold), 0.56 (Glide), 0.51 (Flap) by limiting the enumeration process only to the predicted most stable tautomer. The inclusion of all tautomers (stable and unstable) yielded slightly poorer results than considering only the most stable form in water. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Journal of Chemical Information & Modeling is the property of American Chemical Society and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1021/ci900501c
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        Text: English
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      – SubjectFull: Tautomerism
        Type: general
      – SubjectFull: Drug development
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      – SubjectFull: Virtual reality
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      – SubjectFull: Binding sites
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      – SubjectFull: Protein structure
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      – SubjectFull: Molecular dynamics
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              Text: Jun2010
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