title: A new method for filtering of reactive "warheads" of transition-state analog protease inhibitors.
abstract: 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.
authors.affiliation: The Julius Spokojny Bioorganic Chemistry Laboratory, Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Traube
authors.affiliation: The Julius Spokojny Bioorganic Chemistry Laboratory, Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel. Electronic address: michael.shokhen@biu.ac.il.
authors.forename: Michael
authors.initials: M
authors.lastname: Shokhen
authors.affiliation: The Julius Spokojny Bioorganic Chemistry Laboratory, Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel. Electronic address: amnon.albeck@biu.ac.il.
authors.forename: Amnon
authors.initials: A
authors.lastname: Albeck
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D011480:Protease Inhibitors; D006867:Hydrolases
keywords: Drug design; Enzyme inhibitors; Proteases; Reversible covalent inhibitors; Virtual screening