A new method for filtering of reactive "warheads" of transition-state analog protease inhibitors

Tamar Traube, Michael Shokhen, Amnon Albeck

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


In light of the major contribution of the reactive warhead to the binding energy trend in reversible covalent transition-state analog inhibitors of serine and cysteine hydrolases, would it be possible to rationally design and quickly filter such warheads, especially for large-scale screening? The previously defined W1 and W2 covalent descriptors quantitatively account for the energetic effect of the covalent bonds reorganization, accompanying enzyme-inhibitor covalent binding. The quantum mechanically calculated W1 and W2 reflect the warhead binding energy by modeling of the enzyme-inhibitor reaction core. Here, we demonstrate the use of these descriptors for warhead filtering, and examine its scope and limitations. The W1 and W2 descriptors provide a tool for rational design of various warheads as universal building blocks of real inhibitors without the requirement of 3D structural information about the target enzyme or QSAR studies. These warheads could then be used as hit structural templates in the subsequent optimization of inhibitors recognition sites.

Original languageEnglish
Pages (from-to)134-138
Number of pages5
JournalEuropean Journal of Medicinal Chemistry
StatePublished - 22 Apr 2014

Bibliographical note

Funding Information:
This research was supported by the “ Marcus Center for Pharmaceutical and Medicinal Chemistry ” at Bar Ilan University .


  • Drug design
  • Enzyme inhibitors
  • Proteases
  • Reversible covalent inhibitors
  • Virtual screening


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