Representation of target-bound drugs by computed conformers: implications for conformational libraries
<p>Abstract</p> <p>Background</p> <p>The increasing number of known protein structures provides valuable information about pharmaceutical targets. Drug binding sites are identifiable and suitable lead compounds can be proposed. The flexibility of ligands is a critical p...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2006-06-01
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| Series: | BMC Bioinformatics |
| Online Access: | http://www.biomedcentral.com/1471-2105/7/293 |
| _version_ | 1811275480235507712 |
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| author | Goede Andrean Michalsky Elke Senger Christian Günther Stefan Preissner Robert |
| author_facet | Goede Andrean Michalsky Elke Senger Christian Günther Stefan Preissner Robert |
| author_sort | Goede Andrean |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>The increasing number of known protein structures provides valuable information about pharmaceutical targets. Drug binding sites are identifiable and suitable lead compounds can be proposed. The flexibility of ligands is a critical point for the selection of potential drugs. Since computed 3D structures of millions of compounds are available, the knowledge of their binding conformations would be a great benefit for the development of efficient screening methods.</p> <p>Results</p> <p>Integration of two public databases allowed superposition of conformers for 193 approved drugs with 5507 crystallised target-bound counterparts. The generation of 9600 drug conformers using an atomic force field was carried out to obtain an optimal coverage of the conformational space.</p> <p>Bioactive conformations are best described by a conformational ensemble: half of all drugs exhibit multiple active states, distributed over the entire range of the reachable energy and conformational space.</p> <p>A number of up to 100 conformers per drug enabled us to reproduce the bound states within a similarity threshold of 1.0 Å in 70% of all cases. This fraction rises to about 90% for smaller or average sized drugs.</p> <p>Conclusion</p> <p>Single drugs adopt multiple bioactive conformations if they interact with different target proteins. Due to the structural diversity of binding sites they adopt conformations that are distributed over a broad conformational space and wide energy range. Since the majority of drugs is well represented by a predefined low number of conformers (up to 100) this procedure is a valuable method to compare compounds by three-dimensional features or for fast similarity searches starting with pharmacophores.</p> <p>The underlying 9600 generated drug conformers are downloadable from the Super Drug Web site <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>. All superpositions are visualised at the same source. Additional conformers (110,000) of 2400 classified WHO-drugs are also available.</p> |
| first_indexed | 2024-04-12T23:39:37Z |
| format | Article |
| id | doaj.art-b05afc197921425dac157829386eb8b0 |
| institution | Directory Open Access Journal |
| issn | 1471-2105 |
| language | English |
| last_indexed | 2024-04-12T23:39:37Z |
| publishDate | 2006-06-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Bioinformatics |
| spelling | doaj.art-b05afc197921425dac157829386eb8b02022-12-22T03:12:02ZengBMCBMC Bioinformatics1471-21052006-06-017129310.1186/1471-2105-7-293Representation of target-bound drugs by computed conformers: implications for conformational librariesGoede AndreanMichalsky ElkeSenger ChristianGünther StefanPreissner Robert<p>Abstract</p> <p>Background</p> <p>The increasing number of known protein structures provides valuable information about pharmaceutical targets. Drug binding sites are identifiable and suitable lead compounds can be proposed. The flexibility of ligands is a critical point for the selection of potential drugs. Since computed 3D structures of millions of compounds are available, the knowledge of their binding conformations would be a great benefit for the development of efficient screening methods.</p> <p>Results</p> <p>Integration of two public databases allowed superposition of conformers for 193 approved drugs with 5507 crystallised target-bound counterparts. The generation of 9600 drug conformers using an atomic force field was carried out to obtain an optimal coverage of the conformational space.</p> <p>Bioactive conformations are best described by a conformational ensemble: half of all drugs exhibit multiple active states, distributed over the entire range of the reachable energy and conformational space.</p> <p>A number of up to 100 conformers per drug enabled us to reproduce the bound states within a similarity threshold of 1.0 Å in 70% of all cases. This fraction rises to about 90% for smaller or average sized drugs.</p> <p>Conclusion</p> <p>Single drugs adopt multiple bioactive conformations if they interact with different target proteins. Due to the structural diversity of binding sites they adopt conformations that are distributed over a broad conformational space and wide energy range. Since the majority of drugs is well represented by a predefined low number of conformers (up to 100) this procedure is a valuable method to compare compounds by three-dimensional features or for fast similarity searches starting with pharmacophores.</p> <p>The underlying 9600 generated drug conformers are downloadable from the Super Drug Web site <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>. All superpositions are visualised at the same source. Additional conformers (110,000) of 2400 classified WHO-drugs are also available.</p>http://www.biomedcentral.com/1471-2105/7/293 |
| spellingShingle | Goede Andrean Michalsky Elke Senger Christian Günther Stefan Preissner Robert Representation of target-bound drugs by computed conformers: implications for conformational libraries BMC Bioinformatics |
| title | Representation of target-bound drugs by computed conformers: implications for conformational libraries |
| title_full | Representation of target-bound drugs by computed conformers: implications for conformational libraries |
| title_fullStr | Representation of target-bound drugs by computed conformers: implications for conformational libraries |
| title_full_unstemmed | Representation of target-bound drugs by computed conformers: implications for conformational libraries |
| title_short | Representation of target-bound drugs by computed conformers: implications for conformational libraries |
| title_sort | representation of target bound drugs by computed conformers implications for conformational libraries |
| url | http://www.biomedcentral.com/1471-2105/7/293 |
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