Fragment Merging Using a Graph Database Samples Different Catalogue Space than Similarity Search.
| Autor: | Wills S; Department of Statistics, University of Oxford, Oxford OX1 3LB, United Kingdom.; Centre for Medicines Discovery, University of Oxford, Oxford OX3 7DQ, United Kingdom., Sanchez-Garcia R; Department of Statistics, University of Oxford, Oxford OX1 3LB, United Kingdom.; Centre for Medicines Discovery, University of Oxford, Oxford OX3 7DQ, United Kingdom., Dudgeon T; Informatics Matters, Ltd., Perch Coworking, Franklins House, Bicester OX26 6JU, United Kingdom., Roughley SD; Vernalis (R&D) Limited, Granta Park, Great Abington, Cambridge CB21 6GB, United Kingdom., Merritt A; LifeArc, Lynton House, 7-12 Tavistock Square, London WC1H 9LT, United Kingdom., Hubbard RE; Vernalis (R&D) Limited, Granta Park, Great Abington, Cambridge CB21 6GB, United Kingdom., Davidson J; Vernalis (R&D) Limited, Granta Park, Great Abington, Cambridge CB21 6GB, United Kingdom., von Delft F; Centre for Medicines Discovery, University of Oxford, Oxford OX3 7DQ, United Kingdom.; Diamond Light Source, Didcot OX11 0DE, United Kingdom.; Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, United Kingdom.; Department of Biochemistry, University of Johannesburg, Auckland Park, Johannesburg 2006, South Africa., Deane CM; Department of Statistics, University of Oxford, Oxford OX1 3LB, United Kingdom. |
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| Jazyk: | angličtina |
| Zdroj: | Journal of chemical information and modeling [J Chem Inf Model] 2023 Jun 12; Vol. 63 (11), pp. 3423-3437. Date of Electronic Publication: 2023 May 25. |
| DOI: | 10.1021/acs.jcim.3c00276 |
| Abstrakt: | 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 Mycobacterium tuberculosis EthR inhibitors, potential inhibitors with micromolar IC |
| Databáze: | MEDLINE |
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