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Related Experiment Videos

Site-directed ligand discovery.

D A Erlanson1, A C Braisted, D R Raphael

  • 1Sunesis Pharmaceuticals, Incorporated, Redwood City, CA 94063, USA. erlanson@sunesis-pharma.com

Proceedings of the National Academy of Sciences of the United States of America
|August 16, 2000
PubMed
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A new "tethering" strategy enables discovery of weak-binding ligands for proteins. This method rapidly identifies and optimizes drug leads, as demonstrated by developing a potent thymidylate synthase inhibitor.

Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Drug Discovery

Background:

  • Identifying low molecular weight ligands that bind weakly to target proteins is challenging.
  • Weakly binding ligands often require optimization for therapeutic use.

Purpose of the Study:

  • To develop a novel strategy, termed
  • tethering
  • , for discovering and optimizing weak-binding ligands.
  • To apply this method to identify inhibitors for thymidylate synthase.

Main Methods:

  • Utilizing a reversible reaction between protein cysteine residues and a library of disulfide-containing molecules.
  • Employing mass spectrometry (MS) for ligand identification.
  • Synthesizing analogs based on crystallographic data of tethered complexes.

Related Experiment Videos

Main Results:

  • The tethering method successfully identified ligands that form stable complexes despite weak intrinsic binding.
  • A potent inhibitor for thymidylate synthase was generated, with a 3,000-fold improvement in affinity.
  • Crystallographic structures guided the optimization of lead fragments.

Conclusions:

  • The tethering strategy is effective for discovering and optimizing ligands with weak initial binding affinities.
  • This approach facilitates site-directed drug design by starting with spatially targeted fragments.
  • The method holds promise for developing therapeutics for cancer and infectious diseases.