{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Downes TD"],"funding":["Astex Pharmaceuticals","Pfizer","University of York","AstraZeneca","Horizon 2020;EU Framework Programme for Research and Innovation","Royal Society","Wellcome Trust","Biotechnology and Biological Sciences Research Council"],"pagination":["20030-20041"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12486152"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["16(42)"],"pubmed_abstract":["Fragment-based drug discovery is widely used in both academia and industry during the early stages of drug discovery. There is a growing interest in the design of 3-D fragments for inclusion in fragment libraries in order to increase chemical space coverage. We present herein the design and synthesis of 58 shape-diverse 3-D fragments that are prepared using just three modular synthetic methodologies. The 3-D fragments comprise a cyclic scaffold (cyclopentane, pyrrolidine, piperidine, tetrahydrofuran or tetrahydropyran) with one aromatic or heteroaromatic ring and possess properties within 'rule-of-three' fragment space. 3-D shape is assessed using principal moments of inertia analysis and conformational diversity is achieved by considering all conformations up to 1.5 kcal mol<sup>-1</sup> above the energy of the global minimum energy conformer. Due to the modular nature of the fragment syntheses, these 3-D fragments are synthetically-enabled for fragment elaboration follow-on work, a key design feature. This modular, shape-diverse 3-D fragment collection has delivered privileged starting points across a spectrum of targets. Fragments from the set have been crystallographically validated in the SARS-CoV-2 main protease (M<sup>pro</sup>) and the nonstructural protein 3 (Nsp3) (Mac1) as well as human glycosyltransferase MGATV, a major enzyme in the mammalian <i>N</i>-glycosylation pathway and a promoter of aggressive metastatic cancers, underscoring the breadth of biological space that can be explored."],"journal":["Chemical science"],"pubmed_title":["Design, modular synthesis and screening of 58 shape-diverse 3-D fragments."],"pmcid":["PMC12486152"],"funding_grant_id":["675899","218579/Z/19/Z","BB/N008332/1","INF\\R1\\191028"],"pubmed_authors":["Wrigley GL","Darby JF","Wu L","Jones SP","Vidler LR","Blakemore DC","Davies GJ","Firth JD","Woolford AJ","Whatton MA","Downes TD","De Fusco C","Hubbard RE","Klein HF","Roughley SD","Wang X","Gilio AK","O'Brien P"],"additional_accession":[]},"is_claimable":false,"name":"Design, modular synthesis and screening of 58 shape-diverse 3-D fragments.","description":"Fragment-based drug discovery is widely used in both academia and industry during the early stages of drug discovery. There is a growing interest in the design of 3-D fragments for inclusion in fragment libraries in order to increase chemical space coverage. We present herein the design and synthesis of 58 shape-diverse 3-D fragments that are prepared using just three modular synthetic methodologies. The 3-D fragments comprise a cyclic scaffold (cyclopentane, pyrrolidine, piperidine, tetrahydrofuran or tetrahydropyran) with one aromatic or heteroaromatic ring and possess properties within 'rule-of-three' fragment space. 3-D shape is assessed using principal moments of inertia analysis and conformational diversity is achieved by considering all conformations up to 1.5 kcal mol<sup>-1</sup> above the energy of the global minimum energy conformer. Due to the modular nature of the fragment syntheses, these 3-D fragments are synthetically-enabled for fragment elaboration follow-on work, a key design feature. This modular, shape-diverse 3-D fragment collection has delivered privileged starting points across a spectrum of targets. Fragments from the set have been crystallographically validated in the SARS-CoV-2 main protease (M<sup>pro</sup>) and the nonstructural protein 3 (Nsp3) (Mac1) as well as human glycosyltransferase MGATV, a major enzyme in the mammalian <i>N</i>-glycosylation pathway and a promoter of aggressive metastatic cancers, underscoring the breadth of biological space that can be explored.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Oct","modification":"2026-06-05T09:21:57.182Z","creation":"2026-05-15T03:12:52.475Z"},"accession":"S-EPMC12486152","cross_references":{"pubmed":["41041118"],"doi":["10.1039/d5sc05819h"]}}