biostudies-literatureDownes TDAstex PharmaceuticalsPfizerUniversity of YorkAstraZenecaHorizon 2020;EU Framework Programme for Research and InnovationRoyal SocietyWellcome TrustBiotechnology and Biological Sciences Research Council20030-20041https://www.ebi.ac.uk/biostudies/studies/S-EPMC12486152biostudies-literatureUnknown16(42)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^-1 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^pro) 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.Chemical scienceDesign, modular synthesis and screening of 58 shape-diverse 3-D fragments.PMC12486152675899218579/Z/19/ZBB/N008332/1INF\R1\191028Wrigley GLDarby JFWu LJones SPVidler LRBlakemore DCDavies GJFirth JDWoolford AJWhatton MADownes TDDe Fusco CHubbard REKlein HFRoughley SDWang XGilio AKO'Brien PfalseDesign, modular synthesis and screening of 58 shape-diverse 3-D fragments.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^-1 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^pro) 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.2025-01-01T00:00:00Z2025 Oct2026-06-05T09:21:57.182Z2026-05-15T03:12:52.475ZS-EPMC124861524104111810.1039/d5sc05819h