Toward Atomistic Modeling of Irreversible CovalentInhibitor Binding Kinetics
2019
Covalent inhibitors
have emerged as an important drug class in
recent years, largely due to their many unique advantages as compared
to noncovalent inhibitors, including longer duration of action, lower
prolonged systemic exposure, higher potency, and selectivity. However,
the potential off-target toxicity of covalent inhibitors, particularly
of irreversible covalent inhibitors, represents a great challenge
in covalent drug development. Therefore, accurate calculation of protein
covalent inhibitor reaction kinetics to guide the design of selective
inhibitors would greatly benefit covalent drug discovery efforts.
In the present paper, we present a computational method to calculate
the relative reaction kinetics between congeneric irreversible covalent
inhibitors and their protein receptors. The method combines density
functional theory calculations of the transition state barrier height
of the rate-limiting step for reaction between the warhead of the
inhibitor and a single protein residue, and molecular-mechanics-based
free energy calculations to account for the interactions between the
ligand in the transition state and the protein environment. The method
was tested on four pharmaceutically interesting irreversible covalent
binding systems involving 28 ligands; the mean unsigned error (MUE)
of the relative reaction rate for all pairs of ligands between the
predictions and experimental results for these tested systems is 0.79
log unit. This is to our knowledge the first time where the reaction
kinetics of protein irreversible covalent inhibition have been directly
calculated with physics-based free energy calculation methods and
transition state theory. We anticipate the outstanding accuracy demonstrated
here across a broad range of target classes will have a strong impact
on the design of selective covalent inhibitors.
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