SPR-based fragment screening with neurotensin receptor 1 generates novel small molecule ligands.
The neurotensin receptor 1 represents an important drug target involved in various diseases of the central nervous system. So far, the full exploitation of potential therapeutic activities has been compromised by the lack of compounds with favorable physicochemical and pharmacokinetic properties whi...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5433701?pdf=render |
| _version_ | 1819204033818132480 |
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| author | Sylwia Huber Fabio Casagrande Melanie N Hug Lisha Wang Philipp Heine Lutz Kummer Andreas Plückthun Michael Hennig |
| author_facet | Sylwia Huber Fabio Casagrande Melanie N Hug Lisha Wang Philipp Heine Lutz Kummer Andreas Plückthun Michael Hennig |
| author_sort | Sylwia Huber |
| collection | DOAJ |
| description | The neurotensin receptor 1 represents an important drug target involved in various diseases of the central nervous system. So far, the full exploitation of potential therapeutic activities has been compromised by the lack of compounds with favorable physicochemical and pharmacokinetic properties which efficiently penetrate the blood-brain barrier. Recent progress in the generation of stabilized variants of solubilized neurotensin receptor 1 and its subsequent purification and successful structure determination presents a solid starting point to apply the approach of fragment-based screening to extend the chemical space of known neurotensin receptor 1 ligands. In this report, surface plasmon resonance was used as primary method to screen 6369 compounds. Thereby 44 hits were identified and confirmed in competition as well as dose-response experiments. Furthermore, 4 out of 8 selected hits were validated using nuclear magnetic resonance spectroscopy as orthogonal biophysical method. Computational analysis of the compound structures, taking the known crystal structure of the endogenous peptide agonist into consideration, gave insight into the potential fragment-binding location and interactions and inspires chemistry efforts for further exploration of the fragments. |
| first_indexed | 2024-12-23T04:29:23Z |
| format | Article |
| id | doaj.art-263952a649e24caeb01f9f211d01ff10 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-23T04:29:23Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-263952a649e24caeb01f9f211d01ff102022-12-21T18:00:04ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01125e017584210.1371/journal.pone.0175842SPR-based fragment screening with neurotensin receptor 1 generates novel small molecule ligands.Sylwia HuberFabio CasagrandeMelanie N HugLisha WangPhilipp HeineLutz KummerAndreas PlückthunMichael HennigThe neurotensin receptor 1 represents an important drug target involved in various diseases of the central nervous system. So far, the full exploitation of potential therapeutic activities has been compromised by the lack of compounds with favorable physicochemical and pharmacokinetic properties which efficiently penetrate the blood-brain barrier. Recent progress in the generation of stabilized variants of solubilized neurotensin receptor 1 and its subsequent purification and successful structure determination presents a solid starting point to apply the approach of fragment-based screening to extend the chemical space of known neurotensin receptor 1 ligands. In this report, surface plasmon resonance was used as primary method to screen 6369 compounds. Thereby 44 hits were identified and confirmed in competition as well as dose-response experiments. Furthermore, 4 out of 8 selected hits were validated using nuclear magnetic resonance spectroscopy as orthogonal biophysical method. Computational analysis of the compound structures, taking the known crystal structure of the endogenous peptide agonist into consideration, gave insight into the potential fragment-binding location and interactions and inspires chemistry efforts for further exploration of the fragments.http://europepmc.org/articles/PMC5433701?pdf=render |
| spellingShingle | Sylwia Huber Fabio Casagrande Melanie N Hug Lisha Wang Philipp Heine Lutz Kummer Andreas Plückthun Michael Hennig SPR-based fragment screening with neurotensin receptor 1 generates novel small molecule ligands. PLoS ONE |
| title | SPR-based fragment screening with neurotensin receptor 1 generates novel small molecule ligands. |
| title_full | SPR-based fragment screening with neurotensin receptor 1 generates novel small molecule ligands. |
| title_fullStr | SPR-based fragment screening with neurotensin receptor 1 generates novel small molecule ligands. |
| title_full_unstemmed | SPR-based fragment screening with neurotensin receptor 1 generates novel small molecule ligands. |
| title_short | SPR-based fragment screening with neurotensin receptor 1 generates novel small molecule ligands. |
| title_sort | spr based fragment screening with neurotensin receptor 1 generates novel small molecule ligands |
| url | http://europepmc.org/articles/PMC5433701?pdf=render |
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