Fragment libraries designed to be functionally diverse recover protein binding information more efficiently than standard structurally diverse libraries
Current fragment-based drug design relies on the efficient exploration of chemical space by using structurally diverse libraries of small fragments. However, structurally dissimilar compounds can exploit the same interactions, and thus be functionally similar. Using 3D structures of many fragments b...
| Main Authors: | , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Chemical Society
2022
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| _version_ | 1826310308233216000 |
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| author | Carbery, A Skyner, R von Delft, F Deane, C |
| author_facet | Carbery, A Skyner, R von Delft, F Deane, C |
| author_sort | Carbery, A |
| collection | OXFORD |
| description | Current fragment-based drug design relies on the efficient exploration of chemical space by using structurally diverse libraries of small fragments. However, structurally dissimilar compounds can exploit the
same interactions, and thus be functionally similar. Using 3D structures of many fragments bound to
multiple targets, we examined if there exists a better strategy for selecting fragments for screening libraries. We show that structurally diverse fragments can be described as functionally redundant, often
making the same interactions. Ranking fragments by the number of novel interactions they made, we
show that functionally diverse selections of fragments substantially increase the amount of information
recovered for unseen targets compared to other methods of selection. Using these results, we design small
functionally efficient libraries that are able to give significantly more information about new protein targets than similarly sized structurally diverse libraries. By covering more functional space, more diverse
sets of drug leads can be generated. |
| first_indexed | 2024-03-07T07:50:02Z |
| format | Journal article |
| id | oxford-uuid:7c0b4988-6a63-42fe-8ec9-da364086d2e3 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:50:02Z |
| publishDate | 2022 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:7c0b4988-6a63-42fe-8ec9-da364086d2e32023-07-06T15:01:51ZFragment libraries designed to be functionally diverse recover protein binding information more efficiently than standard structurally diverse librariesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:7c0b4988-6a63-42fe-8ec9-da364086d2e3EnglishSymplectic ElementsAmerican Chemical Society2022Carbery, ASkyner, Rvon Delft, FDeane, CCurrent fragment-based drug design relies on the efficient exploration of chemical space by using structurally diverse libraries of small fragments. However, structurally dissimilar compounds can exploit the same interactions, and thus be functionally similar. Using 3D structures of many fragments bound to multiple targets, we examined if there exists a better strategy for selecting fragments for screening libraries. We show that structurally diverse fragments can be described as functionally redundant, often making the same interactions. Ranking fragments by the number of novel interactions they made, we show that functionally diverse selections of fragments substantially increase the amount of information recovered for unseen targets compared to other methods of selection. Using these results, we design small functionally efficient libraries that are able to give significantly more information about new protein targets than similarly sized structurally diverse libraries. By covering more functional space, more diverse sets of drug leads can be generated. |
| spellingShingle | Carbery, A Skyner, R von Delft, F Deane, C Fragment libraries designed to be functionally diverse recover protein binding information more efficiently than standard structurally diverse libraries |
| title | Fragment libraries designed to be functionally diverse recover protein binding information more efficiently than standard structurally diverse libraries |
| title_full | Fragment libraries designed to be functionally diverse recover protein binding information more efficiently than standard structurally diverse libraries |
| title_fullStr | Fragment libraries designed to be functionally diverse recover protein binding information more efficiently than standard structurally diverse libraries |
| title_full_unstemmed | Fragment libraries designed to be functionally diverse recover protein binding information more efficiently than standard structurally diverse libraries |
| title_short | Fragment libraries designed to be functionally diverse recover protein binding information more efficiently than standard structurally diverse libraries |
| title_sort | fragment libraries designed to be functionally diverse recover protein binding information more efficiently than standard structurally diverse libraries |
| work_keys_str_mv | AT carberya fragmentlibrariesdesignedtobefunctionallydiverserecoverproteinbindinginformationmoreefficientlythanstandardstructurallydiverselibraries AT skynerr fragmentlibrariesdesignedtobefunctionallydiverserecoverproteinbindinginformationmoreefficientlythanstandardstructurallydiverselibraries AT vondelftf fragmentlibrariesdesignedtobefunctionallydiverserecoverproteinbindinginformationmoreefficientlythanstandardstructurallydiverselibraries AT deanec fragmentlibrariesdesignedtobefunctionallydiverserecoverproteinbindinginformationmoreefficientlythanstandardstructurallydiverselibraries |