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

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. [Display omitted] •A new filtering tool for warheads of reversible covalent TS analog inhibitors of proteases.•W1 & W2 covalent descriptors, QM calculated on the enzyme – inhibitor reaction core.•W1 is applicable to serine proteases, and W2 – to cysteine proteases.•W1 & W2: a tool for design of warheads as universal building blocks, without the requirement of 3D structure or QSAR.•The designed warheads can serve as hit templates in subsequent optimization of the inhibitors recognition sites.