Multistate Method to Efficiently Account for Tautomerism and Protonation in Alchemical Free-Energy Calculations
Candide Champion,
Philippe H. Hünenberger,
Sereina Riniker
Abstract:The majority of drug-like
molecules contain at least one ionizable
group, and many common drug scaffolds are subject to tautomeric equilibria.
Thus, these compounds are found in a mixture of protonation and/or
tautomeric states at physiological pH. Intrinsically, standard classical
molecular dynamics (MD) simulations cannot describe such equilibria
between states, which negatively impacts the prediction of key molecular
properties in silico. Following the formalism described
by de Oliveira and co-workers (J. C… Show more
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