Performance evaluation of flexible macrocycle docking in AutoDock
Macrocycles represent an important class of ligands, both in natural products and designed drugs. In drug design, macrocyclizations can impart specific ligand conformations and contribute to passive permeation by encouraging intramolecular H-bonds. AutoDock-GPU and Vina can model macrocyclic ligands...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Cambridge University Press
2022-01-01
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| Series: | QRB Discovery |
| Subjects: | |
| Online Access: | https://www.cambridge.org/core/product/identifier/S2633289222000187/type/journal_article |
| _version_ | 1811155737701777408 |
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| author | Matthew Holcomb Diogo Santos-Martins Andreas F. Tillack Stefano Forli |
| author_facet | Matthew Holcomb Diogo Santos-Martins Andreas F. Tillack Stefano Forli |
| author_sort | Matthew Holcomb |
| collection | DOAJ |
| description | Macrocycles represent an important class of ligands, both in natural products and designed drugs. In drug design, macrocyclizations can impart specific ligand conformations and contribute to passive permeation by encouraging intramolecular H-bonds. AutoDock-GPU and Vina can model macrocyclic ligands flexibly, without requiring the enumeration of macrocyclic conformers before docking. Here, we characterize the performance of the method for handling macrocyclic compounds, which is implemented and the default behaviour for ligand preparation with our ligand preparation pipeline, Meeko. A pseudoatom is used to encode bond geometry and produce an anisotropic closure force for macrocyclic rings. This method is evaluated on a diverse set of small molecule and peptide macrocycles, ranging from 7- to 33-membered rings, showing little accuracy loss compared to rigid redocking of the X-ray macrocycle conformers. This suggests that for conformationally flexible macrocycles with unknown binding modes, this method can be effectively used to predict the macrocycle conformation. |
| first_indexed | 2024-04-10T04:38:37Z |
| format | Article |
| id | doaj.art-6b6ac81b42d749f1ab07da43cc3aeb94 |
| institution | Directory Open Access Journal |
| issn | 2633-2892 |
| language | English |
| last_indexed | 2024-04-10T04:38:37Z |
| publishDate | 2022-01-01 |
| publisher | Cambridge University Press |
| record_format | Article |
| series | QRB Discovery |
| spelling | doaj.art-6b6ac81b42d749f1ab07da43cc3aeb942023-03-09T12:43:36ZengCambridge University PressQRB Discovery2633-28922022-01-01310.1017/qrd.2022.18Performance evaluation of flexible macrocycle docking in AutoDockMatthew Holcomb0https://orcid.org/0000-0002-8409-4344Diogo Santos-Martins1https://orcid.org/0000-0003-4622-3747Andreas F. Tillack2https://orcid.org/0000-0002-1832-3030Stefano Forli3https://orcid.org/0000-0002-5964-7111Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USADepartment of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USADepartment of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USADepartment of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USAMacrocycles represent an important class of ligands, both in natural products and designed drugs. In drug design, macrocyclizations can impart specific ligand conformations and contribute to passive permeation by encouraging intramolecular H-bonds. AutoDock-GPU and Vina can model macrocyclic ligands flexibly, without requiring the enumeration of macrocyclic conformers before docking. Here, we characterize the performance of the method for handling macrocyclic compounds, which is implemented and the default behaviour for ligand preparation with our ligand preparation pipeline, Meeko. A pseudoatom is used to encode bond geometry and produce an anisotropic closure force for macrocyclic rings. This method is evaluated on a diverse set of small molecule and peptide macrocycles, ranging from 7- to 33-membered rings, showing little accuracy loss compared to rigid redocking of the X-ray macrocycle conformers. This suggests that for conformationally flexible macrocycles with unknown binding modes, this method can be effectively used to predict the macrocycle conformation.https://www.cambridge.org/core/product/identifier/S2633289222000187/type/journal_articledockingautodockmacrocycles |
| spellingShingle | Matthew Holcomb Diogo Santos-Martins Andreas F. Tillack Stefano Forli Performance evaluation of flexible macrocycle docking in AutoDock QRB Discovery docking autodock macrocycles |
| title | Performance evaluation of flexible macrocycle docking in AutoDock |
| title_full | Performance evaluation of flexible macrocycle docking in AutoDock |
| title_fullStr | Performance evaluation of flexible macrocycle docking in AutoDock |
| title_full_unstemmed | Performance evaluation of flexible macrocycle docking in AutoDock |
| title_short | Performance evaluation of flexible macrocycle docking in AutoDock |
| title_sort | performance evaluation of flexible macrocycle docking in autodock |
| topic | docking autodock macrocycles |
| url | https://www.cambridge.org/core/product/identifier/S2633289222000187/type/journal_article |
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