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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
Summary
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.
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.