How Diverse Are the Protein-Bound Conformations of Small-Molecule Drugs and Cofactors?
Knowledge of the bioactive conformations of small molecules or the ability to predict them with theoretical methods is of key importance to the design of bioactive compounds such as drugs, agrochemicals, and cosmetics. Using an elaborate cheminformatics pipeline, which also evaluates the support of...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-03-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fchem.2018.00068/full |
| _version_ | 1818549322674864128 |
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| author | Nils-Ole Friedrich Méliné Simsir Méliné Simsir Johannes Kirchmair |
| author_facet | Nils-Ole Friedrich Méliné Simsir Méliné Simsir Johannes Kirchmair |
| author_sort | Nils-Ole Friedrich |
| collection | DOAJ |
| description | Knowledge of the bioactive conformations of small molecules or the ability to predict them with theoretical methods is of key importance to the design of bioactive compounds such as drugs, agrochemicals, and cosmetics. Using an elaborate cheminformatics pipeline, which also evaluates the support of individual atom coordinates by the measured electron density, we compiled a complete set (“Sperrylite Dataset”) of high-quality structures of protein-bound ligand conformations from the PDB. The Sperrylite Dataset consists of a total of 10,936 high-quality structures of 4,548 unique ligands. Based on this dataset, we assessed the variability of the bioactive conformations of 91 small molecules—each represented by a minimum of ten structures—and found it to be largely independent of the number of rotatable bonds. Sixty-nine molecules had at least two distinct conformations (defined by an RMSD greater than 1 Å). For a representative subset of 17 approved drugs and cofactors we observed a clear trend for the formation of few clusters of highly similar conformers. Even for proteins that share a very low sequence identity, ligands were regularly found to adopt similar conformations. For cofactors, a clear trend for extended conformations was measured, although in few cases also coiled conformers were observed. The Sperrylite Dataset is available for download from http://www.zbh.uni-hamburg.de/sperrylite_dataset. |
| first_indexed | 2024-12-12T08:31:51Z |
| format | Article |
| id | doaj.art-d18f82932f6c4522aa8a843f59058bd8 |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-12-12T08:31:51Z |
| publishDate | 2018-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-d18f82932f6c4522aa8a843f59058bd82022-12-22T00:31:05ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462018-03-01610.3389/fchem.2018.00068340732How Diverse Are the Protein-Bound Conformations of Small-Molecule Drugs and Cofactors?Nils-Ole Friedrich0Méliné Simsir1Méliné Simsir2Johannes Kirchmair3Department of Informatics, Center for Bioinformatics, Universität Hamburg, Hamburg, GermanyDepartment of Informatics, Center for Bioinformatics, Universität Hamburg, Hamburg, GermanyMolécules Thérapeutiques In Silico, Université Paris Diderot, Sorbonne Paris Cité, Paris, FranceDepartment of Informatics, Center for Bioinformatics, Universität Hamburg, Hamburg, GermanyKnowledge of the bioactive conformations of small molecules or the ability to predict them with theoretical methods is of key importance to the design of bioactive compounds such as drugs, agrochemicals, and cosmetics. Using an elaborate cheminformatics pipeline, which also evaluates the support of individual atom coordinates by the measured electron density, we compiled a complete set (“Sperrylite Dataset”) of high-quality structures of protein-bound ligand conformations from the PDB. The Sperrylite Dataset consists of a total of 10,936 high-quality structures of 4,548 unique ligands. Based on this dataset, we assessed the variability of the bioactive conformations of 91 small molecules—each represented by a minimum of ten structures—and found it to be largely independent of the number of rotatable bonds. Sixty-nine molecules had at least two distinct conformations (defined by an RMSD greater than 1 Å). For a representative subset of 17 approved drugs and cofactors we observed a clear trend for the formation of few clusters of highly similar conformers. Even for proteins that share a very low sequence identity, ligands were regularly found to adopt similar conformations. For cofactors, a clear trend for extended conformations was measured, although in few cases also coiled conformers were observed. The Sperrylite Dataset is available for download from http://www.zbh.uni-hamburg.de/sperrylite_dataset.http://journal.frontiersin.org/article/10.3389/fchem.2018.00068/fullbioactive conformational spaceprotein-bound ligand conformationconformational variabilityPDBprotein-ligand interactionbinding site |
| spellingShingle | Nils-Ole Friedrich Méliné Simsir Méliné Simsir Johannes Kirchmair How Diverse Are the Protein-Bound Conformations of Small-Molecule Drugs and Cofactors? Frontiers in Chemistry bioactive conformational space protein-bound ligand conformation conformational variability PDB protein-ligand interaction binding site |
| title | How Diverse Are the Protein-Bound Conformations of Small-Molecule Drugs and Cofactors? |
| title_full | How Diverse Are the Protein-Bound Conformations of Small-Molecule Drugs and Cofactors? |
| title_fullStr | How Diverse Are the Protein-Bound Conformations of Small-Molecule Drugs and Cofactors? |
| title_full_unstemmed | How Diverse Are the Protein-Bound Conformations of Small-Molecule Drugs and Cofactors? |
| title_short | How Diverse Are the Protein-Bound Conformations of Small-Molecule Drugs and Cofactors? |
| title_sort | how diverse are the protein bound conformations of small molecule drugs and cofactors |
| topic | bioactive conformational space protein-bound ligand conformation conformational variability PDB protein-ligand interaction binding site |
| url | http://journal.frontiersin.org/article/10.3389/fchem.2018.00068/full |
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