Syndirella: synthesis-directed fragment elaboration enables extensive and cost-effective binding site exploration beyond catalog compounds
6 affiliations
- 1Oxford Protein Informatics Group, Department of Statistics, University of Oxford Oxford OX1 3LB UK
- 2Research Complex at Harwell Harwell Science and Innovation Campus Didcot OX11 0FA UK
- 3Centre for Medicines Discovery, University of Oxford Oxford OX3 7DQ UK
- 4Diamond Light Source Harwell Science and Innovation Campus Didcot OX11 0QX UK
- 5IBM TJ Watson Research Center, IBM Research 1101 Kitchawan Rd, Yorktown Heights NY 10598 USA
- 6Department of Biochemistry, University of Johannesburg Auckland Park Johannesburg 2006 South Africa
Abstract
Fragment screens provide an information-rich starting point for designing derivative compounds in structure-based drug discovery. However, derivatives in the fragment-to-hit stage are typically designed from only one or a few fragments, risking premature convergence on an unproductive series and dramatically limiting exploration of the binding site's interaction opportunities. This is avoidable by exploring a broad, chemically diverse set of scaffolds and elaborations spanning interactions revealed across many fragments, as well as those not yet observed. Conventional catalog procurement makes this breadth of testing prohibitively expensive for early discovery. In-house high-throughput (HT) synthesis can raise interaction productivity, the number of unique predicted protein–ligand interactions achievable within a given budget, by lowering the cost per compound, including labor and consumables, yet no design tool exists for this purpose. We introduce Syndirella (Synthesis Directed Elaborations), which presents a candidate elaboration space around input fragment-derived scaffolds, constrained to HT-compatible reactions and catalog reactants, for cost-effective sampling of many scaffolds' elaborations in a single experimental cycle. Applied to three viral protein targets, Syndirella designs demonstrated pharmacophore diversity, recapitulating known fragment interactions, identifying novel functionally relevant ones, and accessing chemical space absent from commercial catalogs. A companion paper details validation on a calcium-binding protein, yielding crystallographic structures and measurable binding, with in-house synthesis achieving a 71% cost reduction over catalog purchasing, labor and consumables included. Reactant rather than product procurement gives potentially 2.5 times as many accessible compounds and higher interaction productivity for the same budget. Syndirella is most impactful for structure-enabled campaigns with fragment-bound crystal structures, robust HT chemistry, and assays compatible with crude reaction mixtures, and is available at https://github.com/oxpig/syndirella.
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BibTeX
@article{fieseler2026syndirella,
title = {{Syndirella: synthesis-directed fragment elaboration enables extensive and cost-effective binding site exploration beyond catalog compounds}},
author = {Kate K. Fieseler and Max Winokan and Joseph A. Morrone and Charlotte M. Deane and Frank von Delft and Warren Thompson},
journal = {Chemical science},
year = {2026},
month = sep,
doi = {10.1039/d6sc02032a},
url = {https://europepmc.org/article/PMC/PMC13656017},
note = {CC BY},
}
RIS
TY - JOUR
TI - Syndirella: synthesis-directed fragment elaboration enables extensive and cost-effective binding site exploration beyond catalog compounds
AU - Kate K. Fieseler
AU - Max Winokan
AU - Joseph A. Morrone
AU - Charlotte M. Deane
AU - Frank von Delft
AU - Warren Thompson
PY - 2026
DA - 2026/09/29
JO - Chemical science
DO - 10.1039/d6sc02032a
UR - https://europepmc.org/article/PMC/PMC13656017
AB - Fragment screens provide an information-rich starting point for designing derivative compounds in structure-based drug discovery. However, derivatives in the fragment-to-hit stage are typically designed from only one or a few fragments, risking premature convergence on an unproductive series and dramatically limiting exploration of the binding site's interaction opportunities. This is avoidable by exploring a broad, chemically diverse set of scaffolds and elaborations spanning interactions revealed across many fragments, as well as those not yet observed. Conventional catalog procurement makes this breadth of testing prohibitively expensive for early discovery. In-house high-throughput (HT) synthesis can raise interaction productivity, the number of unique predicted protein–ligand interactions achievable within a given budget, by lowering the cost per compound, including labor and consumables, yet no design tool exists for this purpose. We introduce Syndirella (Synthesis Directed Elaborations), which presents a candidate elaboration space around input fragment-derived scaffolds, constrained to HT-compatible reactions and catalog reactants, for cost-effective sampling of many scaffolds' elaborations in a single experimental cycle. Applied to three viral protein targets, Syndirella designs demonstrated pharmacophore diversity, recapitulating known fragment interactions, identifying novel functionally relevant ones, and accessing chemical space absent from commercial catalogs. A companion paper details validation on a calcium-binding protein, yielding crystallographic structures and measurable binding, with in-house synthesis achieving a 71% cost reduction over catalog purchasing, labor and consumables included. Reactant rather than product procurement gives potentially 2.5 times as many accessible compounds and higher interaction productivity for the same budget. Syndirella is most impactful for structure-enabled campaigns with fragment-bound crystal structures, robust HT chemistry, and assays compatible with crude reaction mixtures, and is available at https://github.com/oxpig/syndirella.
SN - 2041-6520
SN - 2041-6539
ER -