1nme Citations

In situ assembly of enzyme inhibitors using extended tethering.

Nat Biotechnol 21 308-14 (2003)
Related entries: 1nmq, 1nms

Cited: 105 times
EuropePMC logo PMID: 12563278

Abstract

Cysteine aspartyl protease-3 (caspase-3) is a mediator of apoptosis and a therapeutic target for a wide range of diseases. Using a dynamic combinatorial technology, 'extended tethering', we identified unique nonpeptidic inhibitors for this enzyme. Extended tethering allowed the identification of ligands that bind to discrete regions of caspase-3 and also helped direct the assembly of these ligands into small-molecule inhibitors. We first designed a small-molecule 'extender' that irreversibly alkylates the cysteine residue of caspase-3 and also contains a thiol group. The modified protein was then screened against a library of disulfide-containing small-molecule fragments. Mass-spectrometry was used to identify ligands that bind noncovalently to the protein and that also form a disulfide linkage with the extender. Linking the selected fragments with binding elements from the extenders generates reversible, tight-binding molecules that are druglike and distinct from known inhibitors. One molecule derived from this approach inhibited apoptosis in cells.

Reviews - 1nme mentioned but not cited (2)

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Articles - 1nme mentioned but not cited (24)

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Reviews citing this publication (34)

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Related citations provided by authors (1)

  1. Identification of Potent and Selective Small-Molecule Inhibitors of Caspase-3 through the Use of Extended Tethering and Structure-Based Drug Design. Choong IC, Lew W, Lee D, Pham P, Burdett MT, Lam JW, Wiesmann C, Luong TN, Fahr B, O'Brian T J. Med. Chem. 45 5005-5022 (2002)