Exploring protein hotspots by optimized fragment pharmacophores
Fragment-based drug design has introduced a bottom-up process for drug development, with improved sampling of chemical space and increased effectiveness in early drug discovery. Here, we combine the use of pharmacophores, the most general concept of representing drug-target interactions with the the...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2021
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| _version_ | 1797100261138759680 |
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| author | Bajusz, D Wade, WS Satała, G Bojarski, AJ Ilaš, J Ebner, J Grebien, F Papp, H Jakab, F Douangamath, A Fearon, D von Delft, F Schuller, M Ahel, I Wakefield, A Vajda, S Gerencsér, J Pallai, P Keserű, GM |
| author_facet | Bajusz, D Wade, WS Satała, G Bojarski, AJ Ilaš, J Ebner, J Grebien, F Papp, H Jakab, F Douangamath, A Fearon, D von Delft, F Schuller, M Ahel, I Wakefield, A Vajda, S Gerencsér, J Pallai, P Keserű, GM |
| author_sort | Bajusz, D |
| collection | OXFORD |
| description | Fragment-based drug design has introduced a bottom-up process for drug development, with improved sampling of chemical space and increased effectiveness in early drug discovery. Here, we combine the use of pharmacophores, the most general concept of representing drug-target interactions with the theory of protein hotspots, to develop a design protocol for fragment libraries. The SpotXplorer approach compiles small fragment libraries that maximize the coverage of experimentally confirmed binding pharmacophores at the most preferred hotspots. The efficiency of this approach is demonstrated with a pilot library of 96 fragment-sized compounds (SpotXplorer0) that is validated on popular target classes and emerging drug targets. Biochemical screening against a set of GPCRs and proteases retrieves compounds containing an average of 70% of known pharmacophores for these targets. More importantly, SpotXplorer0 screening identifies confirmed hits against recently established challenging targets such as the histone methyltransferase SETD2, the main protease (3CLPro) and the NSP3 macrodomain of SARS-CoV-2. |
| first_indexed | 2024-03-07T05:35:12Z |
| format | Journal article |
| id | oxford-uuid:e3a66be9-3502-4412-a286-b653bd197d95 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:35:12Z |
| publishDate | 2021 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:e3a66be9-3502-4412-a286-b653bd197d952022-03-27T10:10:47ZExploring protein hotspots by optimized fragment pharmacophoresJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e3a66be9-3502-4412-a286-b653bd197d95EnglishSymplectic ElementsSpringer Nature2021Bajusz, DWade, WSSatała, GBojarski, AJIlaš, JEbner, JGrebien, FPapp, HJakab, FDouangamath, AFearon, Dvon Delft, FSchuller, MAhel, IWakefield, AVajda, SGerencsér, JPallai, PKeserű, GMFragment-based drug design has introduced a bottom-up process for drug development, with improved sampling of chemical space and increased effectiveness in early drug discovery. Here, we combine the use of pharmacophores, the most general concept of representing drug-target interactions with the theory of protein hotspots, to develop a design protocol for fragment libraries. The SpotXplorer approach compiles small fragment libraries that maximize the coverage of experimentally confirmed binding pharmacophores at the most preferred hotspots. The efficiency of this approach is demonstrated with a pilot library of 96 fragment-sized compounds (SpotXplorer0) that is validated on popular target classes and emerging drug targets. Biochemical screening against a set of GPCRs and proteases retrieves compounds containing an average of 70% of known pharmacophores for these targets. More importantly, SpotXplorer0 screening identifies confirmed hits against recently established challenging targets such as the histone methyltransferase SETD2, the main protease (3CLPro) and the NSP3 macrodomain of SARS-CoV-2. |
| spellingShingle | Bajusz, D Wade, WS Satała, G Bojarski, AJ Ilaš, J Ebner, J Grebien, F Papp, H Jakab, F Douangamath, A Fearon, D von Delft, F Schuller, M Ahel, I Wakefield, A Vajda, S Gerencsér, J Pallai, P Keserű, GM Exploring protein hotspots by optimized fragment pharmacophores |
| title | Exploring protein hotspots by optimized fragment pharmacophores |
| title_full | Exploring protein hotspots by optimized fragment pharmacophores |
| title_fullStr | Exploring protein hotspots by optimized fragment pharmacophores |
| title_full_unstemmed | Exploring protein hotspots by optimized fragment pharmacophores |
| title_short | Exploring protein hotspots by optimized fragment pharmacophores |
| title_sort | exploring protein hotspots by optimized fragment pharmacophores |
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