2026-09-14 · Thrombin / hit-finding via dynamic combinatorial chemistry (DCC), trivalent ligand design · Angewandte Chemie International Edition (Wiley) Angew. Chem. Int. Ed. 2026, 65 (38)

Dynamic Chemical Library Yields Sub-Picomolar Thrombin Inhibitor

dynamic combinatorial chemistrythrombin inhibitorhit-findingtrivalent ligandexositePNA-templated libraryMALDI-MS screening

Researchers applied dynamic combinatorial chemistry (DCC), a hit-finding method in which reversible chemical building blocks assemble and reassemble under target guidance, letting the biological target itself select its best-binding partners.
A new platform uses short peptide nucleic acid (PNA) tags to template three-fragment combinations, generating a library of 125,000 possible trivalent assemblies screened against thrombin.
Candidate complexes are isolated by size-exclusion filtration and identified by MALDI mass spectrometry, compressing an entire selection-and-readout cycle to under an hour.
Thrombin favored combinations engaging its active site and both flanking exosites at once, and this trivalent binding mode underlies the exceptionally tight affinity.
The winning assembly is a fully reversible inhibitor with sub-picomolar affinity, achieving near-stoichiometric inhibition of thrombin activity.

💡 Points

DCC keeps getting overshadowed by DEL and FBDD, but this is the kind of result that should change that — a sub-hour select-and-read cycle via PNA templating plus MALDI readout tackles the real bottleneck that's always killed DCC in practice: slow kinetics and painful analytics. What actually earns the affinity isn't luck, though — it's rational exploitation of thrombin's well-mapped exosite architecture, deliberately building a trivalent ligand that bridges the active site and both exosites simultaneously. That's textbook multivalency applied with real target knowledge. My immediate skepticism: a PNA-templated trivalent assembly hitting sub-picomolar affinity is almost certainly a big, charged, un-drug-like molecule — I'd want MW, PK, and oral bioavailability numbers before getting excited about anything beyond a tool compound or long-acting parenteral candidate. Still, as a proof of concept for DCC against other exosite-rich or multi-pocket targets, this is a template worth stealing.

Discovery of a Reversible Sub‐Picomolar Thrombin Inhibitor Using DCC ↗