1 research outputs found
Quantum Mechanics-Based Scoring Rationalizes the Irreversible Inactivation of Parasitic <i>Schistosoma mansoni</i> Cysteine Peptidase by Vinyl Sulfone Inhibitors
The
quantum mechanics (QM)-based scoring function that we previously
developed for the description of noncovalent binding in protein–ligand
complexes has been modified and extended to treat covalent binding
of inhibitory ligands. The enhancements are (i) the description of
the covalent bond breakage and formation using hybrid QM/semiempirical
QM (QM/SQM) restrained optimizations and (ii) the addition of the
new Δ<i>G</i><sub>cov</sub>′ term to the noncovalent
score, describing the “free” energy difference between
the covalent and noncovalent complexes. This enhanced QM-based scoring
function is applied to a series of 20 vinyl sulfone-based inhibitory
compounds inactivating the cysteine peptidase cathepsin B1 of the Schistosoma mansoni parasite (SmCB1). The available
X-ray structure of the SmCB1 in complex with a potent vinyl sulfone
inhibitor K11017 is used as a template to build the other covalently
bound complexes and to model the derived noncovalent complexes. We
present the correlation of the covalent score and its constituents
with the experimental binding data. Four outliers are identified.
They contain bulky R<sub>1</sub>′ substituents structurally
divergent from the template, which might induce larger protein rearrangements
than could be accurately modeled. In summary, we propose a new computational
approach and an optimal protocol for the rapid evaluation and prospective
design of covalent inhibitors with a conserved binding mode