Fragment merging using a graph database samples different catalogue space than similarity search
Fragment merging is a promising approach to progressing fragments directly to on-scale potency: each designed compound incorporates the structural motifs of overlapping fragments in a way that ensures compounds recapitulate multiple high-quality interactions. Searching commercial catalogues provides...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Chemical Society
2023
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| Subjects: |
| _version_ | 1826310955889328128 |
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| author | Wills, S Sanchez-Garcia, R Dudgeon, T Roughley, SD Merritt, A Hubbard, RE Davidson, J Von Delft, F Deane, CM |
| author_facet | Wills, S Sanchez-Garcia, R Dudgeon, T Roughley, SD Merritt, A Hubbard, RE Davidson, J Von Delft, F Deane, CM |
| author_sort | Wills, S |
| collection | OXFORD |
| description | Fragment merging is a promising approach to progressing fragments directly to on-scale potency: each designed compound incorporates the structural motifs of overlapping fragments in a way that ensures compounds recapitulate multiple high-quality interactions. Searching commercial catalogues provides one useful way to quickly and cheaply identify such merges and circumvents the challenge of synthetic accessibility, provided they can be readily identified. Here, we demonstrate that the Fragment Network, a graph database that provides a novel way to explore the chemical space surrounding fragment hits, is well-suited to this challenge. We use an iteration of the database containing >120 million catalogue compounds to find fragment merges for four crystallographic screening campaigns and contrast the results with a traditional fingerprint-based similarity search. The two approaches identify complementary sets of merges that recapitulate the observed fragment–protein interactions but lie in different regions of chemical space. We further show our methodology is an effective route to achieving on-scale potency by retrospective analyses for two different targets; in analyses of public COVID Moonshot and <i>Mycobacterium tuberculosis</i> EthR inhibitors, potential inhibitors with micromolar IC<sub>50</sub> values were identified. This work demonstrates the use of the Fragment Network to increase the yield of fragment merges beyond that of a classical catalogue search. |
| first_indexed | 2024-03-07T08:01:12Z |
| format | Journal article |
| id | oxford-uuid:e382abb4-5584-4dc4-9b81-9dbcb7def9e2 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:01:12Z |
| publishDate | 2023 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:e382abb4-5584-4dc4-9b81-9dbcb7def9e22023-09-26T12:50:27ZFragment merging using a graph database samples different catalogue space than similarity searchJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e382abb4-5584-4dc4-9b81-9dbcb7def9e2MoleculesPeptides and proteinsConformationFiltrationBiological databasesEnglishSymplectic ElementsAmerican Chemical Society2023Wills, SSanchez-Garcia, RDudgeon, TRoughley, SDMerritt, AHubbard, REDavidson, JVon Delft, FDeane, CMFragment merging is a promising approach to progressing fragments directly to on-scale potency: each designed compound incorporates the structural motifs of overlapping fragments in a way that ensures compounds recapitulate multiple high-quality interactions. Searching commercial catalogues provides one useful way to quickly and cheaply identify such merges and circumvents the challenge of synthetic accessibility, provided they can be readily identified. Here, we demonstrate that the Fragment Network, a graph database that provides a novel way to explore the chemical space surrounding fragment hits, is well-suited to this challenge. We use an iteration of the database containing >120 million catalogue compounds to find fragment merges for four crystallographic screening campaigns and contrast the results with a traditional fingerprint-based similarity search. The two approaches identify complementary sets of merges that recapitulate the observed fragment–protein interactions but lie in different regions of chemical space. We further show our methodology is an effective route to achieving on-scale potency by retrospective analyses for two different targets; in analyses of public COVID Moonshot and <i>Mycobacterium tuberculosis</i> EthR inhibitors, potential inhibitors with micromolar IC<sub>50</sub> values were identified. This work demonstrates the use of the Fragment Network to increase the yield of fragment merges beyond that of a classical catalogue search. |
| spellingShingle | Molecules Peptides and proteins Conformation Filtration Biological databases Wills, S Sanchez-Garcia, R Dudgeon, T Roughley, SD Merritt, A Hubbard, RE Davidson, J Von Delft, F Deane, CM Fragment merging using a graph database samples different catalogue space than similarity search |
| title | Fragment merging using a graph database samples different catalogue space than similarity search |
| title_full | Fragment merging using a graph database samples different catalogue space than similarity search |
| title_fullStr | Fragment merging using a graph database samples different catalogue space than similarity search |
| title_full_unstemmed | Fragment merging using a graph database samples different catalogue space than similarity search |
| title_short | Fragment merging using a graph database samples different catalogue space than similarity search |
| title_sort | fragment merging using a graph database samples different catalogue space than similarity search |
| topic | Molecules Peptides and proteins Conformation Filtration Biological databases |
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