PubChem3D: conformer ensemble accuracy
<p>Abstract</p> <p>Background</p> <p>PubChem is a free and publicly available resource containing substance descriptions and their associated biological activity information. PubChem3D is an extension to PubChem containing computationally-derived three-dimensional (3-D)...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2013-01-01
|
| Series: | Journal of Cheminformatics |
| Online Access: | http://www.jcheminf.com/content/5/1/1 |
| _version_ | 1818917520094003200 |
|---|---|
| author | Kim Sunghwan Bolton Evan E Bryant Stephen H |
| author_facet | Kim Sunghwan Bolton Evan E Bryant Stephen H |
| author_sort | Kim Sunghwan |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>PubChem is a free and publicly available resource containing substance descriptions and their associated biological activity information. PubChem3D is an extension to PubChem containing computationally-derived three-dimensional (3-D) structures of small molecules. All the tools and services that are a part of PubChem3D rely upon the quality of the 3-D conformer models. Construction of the conformer models currently available in PubChem3D involves a clustering stage to sample the conformational space spanned by the molecule. While this stage allows one to downsize the conformer models to more manageable size, it may result in a loss of the ability to reproduce experimentally determined “bioactive” conformations, for example, found for PDB ligands. This study examines the extent of this accuracy loss and considers its effect on the 3-D similarity analysis of molecules.</p> <p>Results</p> <p>The conformer models consisting of up to 100,000 conformers per compound were generated for 47,123 small molecules whose structures were experimentally determined, and the conformers in each conformer model were clustered to reduce the size of the conformer model to a maximum of 500 conformers per molecule. The accuracy of the conformer models before and after clustering was evaluated using five different measures: root-mean-square distance (RMSD), shape-optimized shape-Tanimoto (<it>ST</it><sup><it>ST-opt</it></sup>) and combo-Tanimoto (<it>ComboT</it><sup><it>ST-opt</it></sup>), and color-optimized color-Tanimoto (<it>CT</it><sup><it>CT-opt</it></sup>) and combo-Tanimoto (<it>ComboT</it><sup><it>CT-opt</it></sup>). On average, the effect of clustering decreased the conformer model accuracy, increasing the conformer ensemble’s RMSD to the bioactive conformer (by 0.18 ± 0.12 Å), and decreasing the <it>ST</it><sup><it>ST-opt</it></sup>, <it>ComboT</it><sup><it>ST-opt</it></sup>, <it>CT</it><sup><it>CT-opt</it></sup>, and <it>ComboT</it><sup><it>CT-opt</it></sup> scores (by 0.04 ± 0.03, 0.16 ± 0.09, 0.09 ± 0.05, and 0.15 ± 0.09, respectively).</p> <p>Conclusion</p> <p>This study shows the RMSD accuracy performance of the PubChem3D conformer models is operating as designed. In addition, the effect of PubChem3D sampling on 3-D similarity measures shows that there is a linear degradation of average accuracy with respect to molecular size and flexibility. Generally speaking, one can likely expect the worst-case minimum accuracy of 90% or more of the PubChem3D ensembles to be 0.75, 1.09, 0.43, and 1.13, in terms of <it>ST</it><sup><it>ST-opt</it></sup>, <it>ComboT</it><sup><it>ST-opt</it></sup>, <it>CT</it><sup><it>CT-opt</it></sup>, and <it>ComboT</it><sup><it>CT-opt</it></sup>, respectively. This expected accuracy improves linearly as the molecule becomes smaller or less flexible.</p> |
| first_indexed | 2024-12-20T00:35:22Z |
| format | Article |
| id | doaj.art-b5111ecaea8241259801756773061488 |
| institution | Directory Open Access Journal |
| issn | 1758-2946 |
| language | English |
| last_indexed | 2024-12-20T00:35:22Z |
| publishDate | 2013-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Cheminformatics |
| spelling | doaj.art-b5111ecaea82412598017567730614882022-12-21T19:59:46ZengBMCJournal of Cheminformatics1758-29462013-01-0151110.1186/1758-2946-5-1PubChem3D: conformer ensemble accuracyKim SunghwanBolton Evan EBryant Stephen H<p>Abstract</p> <p>Background</p> <p>PubChem is a free and publicly available resource containing substance descriptions and their associated biological activity information. PubChem3D is an extension to PubChem containing computationally-derived three-dimensional (3-D) structures of small molecules. All the tools and services that are a part of PubChem3D rely upon the quality of the 3-D conformer models. Construction of the conformer models currently available in PubChem3D involves a clustering stage to sample the conformational space spanned by the molecule. While this stage allows one to downsize the conformer models to more manageable size, it may result in a loss of the ability to reproduce experimentally determined “bioactive” conformations, for example, found for PDB ligands. This study examines the extent of this accuracy loss and considers its effect on the 3-D similarity analysis of molecules.</p> <p>Results</p> <p>The conformer models consisting of up to 100,000 conformers per compound were generated for 47,123 small molecules whose structures were experimentally determined, and the conformers in each conformer model were clustered to reduce the size of the conformer model to a maximum of 500 conformers per molecule. The accuracy of the conformer models before and after clustering was evaluated using five different measures: root-mean-square distance (RMSD), shape-optimized shape-Tanimoto (<it>ST</it><sup><it>ST-opt</it></sup>) and combo-Tanimoto (<it>ComboT</it><sup><it>ST-opt</it></sup>), and color-optimized color-Tanimoto (<it>CT</it><sup><it>CT-opt</it></sup>) and combo-Tanimoto (<it>ComboT</it><sup><it>CT-opt</it></sup>). On average, the effect of clustering decreased the conformer model accuracy, increasing the conformer ensemble’s RMSD to the bioactive conformer (by 0.18 ± 0.12 Å), and decreasing the <it>ST</it><sup><it>ST-opt</it></sup>, <it>ComboT</it><sup><it>ST-opt</it></sup>, <it>CT</it><sup><it>CT-opt</it></sup>, and <it>ComboT</it><sup><it>CT-opt</it></sup> scores (by 0.04 ± 0.03, 0.16 ± 0.09, 0.09 ± 0.05, and 0.15 ± 0.09, respectively).</p> <p>Conclusion</p> <p>This study shows the RMSD accuracy performance of the PubChem3D conformer models is operating as designed. In addition, the effect of PubChem3D sampling on 3-D similarity measures shows that there is a linear degradation of average accuracy with respect to molecular size and flexibility. Generally speaking, one can likely expect the worst-case minimum accuracy of 90% or more of the PubChem3D ensembles to be 0.75, 1.09, 0.43, and 1.13, in terms of <it>ST</it><sup><it>ST-opt</it></sup>, <it>ComboT</it><sup><it>ST-opt</it></sup>, <it>CT</it><sup><it>CT-opt</it></sup>, and <it>ComboT</it><sup><it>CT-opt</it></sup>, respectively. This expected accuracy improves linearly as the molecule becomes smaller or less flexible.</p>http://www.jcheminf.com/content/5/1/1 |
| spellingShingle | Kim Sunghwan Bolton Evan E Bryant Stephen H PubChem3D: conformer ensemble accuracy Journal of Cheminformatics |
| title | PubChem3D: conformer ensemble accuracy |
| title_full | PubChem3D: conformer ensemble accuracy |
| title_fullStr | PubChem3D: conformer ensemble accuracy |
| title_full_unstemmed | PubChem3D: conformer ensemble accuracy |
| title_short | PubChem3D: conformer ensemble accuracy |
| title_sort | pubchem3d conformer ensemble accuracy |
| url | http://www.jcheminf.com/content/5/1/1 |
| work_keys_str_mv | AT kimsunghwan pubchem3dconformerensembleaccuracy AT boltonevane pubchem3dconformerensembleaccuracy AT bryantstephenh pubchem3dconformerensembleaccuracy |