2. Academic Validation
  3. Deconstruction of Dual-Site Tankyrase Inhibitors Provides Insights into Binding Energetics and Suggests Critical Hotspots for Ligand Optimization

Deconstruction of Dual-Site Tankyrase Inhibitors Provides Insights into Binding Energetics and Suggests Critical Hotspots for Ligand Optimization

  • J Med Chem. 2025 Apr 10;68(7):7263-7279. doi: 10.1021/acs.jmedchem.4c02845.
Sven T Sowa 1,  Murat Kücükdisli 2,  Yelena Mostinski 2,  David A Schaller 3,  Carolina S Vinagreiro 2,  Davide Cirillo 2,  Chiara Bosetti 1,  Shoshy Alam Brinch 4 5,  Kirsten van Laar 6,  Anita Wegert 6,  Ruben G G Leenders 6,  Stefan Krauss 4 5,  Jo Waaler 4 5,  Andrea Volkamer 3 7,  Lari Lehtiö 1,  Marc Nazaré 2
Affiliations

Affiliations

  • 1 Faculty for Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Aapistie 7, 90220 Oulu, Finland.
  • 2 Medicinal Chemistry, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Campus Berlin Buch, Robert-Roessle-Str. 10, 13125 Berlin, Germany.
  • 3 In Silico Toxicology and Structural Bioinformatics, Institute of Physiology, Charité Universitätsmedizin Berlin, Virchowweg 6, 10117 Berlin, Germany.
  • 4 Oslo University Hospital, P.O. Box 4950, Nydalen, 0424 Oslo, Norway.
  • 5 Hybrid Technology Hub─Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway.
  • 6 Symeres Netherlands B.V., Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands.
  • 7 Data Driven Drug Design, Faculty of Mathematics and Computer Sciences, Saarland University, 66123 Saarbrücken, Germany.
PMID: 40134122 DOI: 10.1021/acs.jmedchem.4c02845
Abstract

Designing inhibitors is a complex task that requires a deep understanding of protein-ligand interactions and their dynamics. Ligands often interact with multiple binding subsites, with noncovalent interactions affecting binding affinity. Conformational changes and plasticity of both, the ligand and the protein influence binding energetics. We investigated the tankyrase ADP-ribosyltransferase as a promising drug target regulating many cellular pathways. Despite the existence of diverse tankyrase inhibitors, their binding energetics and contributions of flexible cryptic subpockets to binding affinity remain elusive. To examine these aspects, we deconstructed inhibitors to key fragments, dissected their energetic contribution to the affinity, and determined their binding mode by X-ray crystallography. Varying ligand efficiencies of the deconstructed, pocket-binding fragments revealed the cryptic nature of subpockets. These insights enabled us to redesign inhibitors with novel linkers, the observed key area for optimization, increasing the potency in enzymatic and cell-based assays by 7.5-fold and 6.2-fold compared to the parent ligand.

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  • HY-173480
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