Monitoring
Drug Self-Aggregation and Potential for
Promiscuity in Off-Target In Vitro Pharmacology Screens by a Practical
NMR Strategy
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Abstract
A simple
NMR assay was applied to monitor the tendency of compounds
to self-aggregate in aqueous media. The observation of unusual spectral
trends as a function of compound concentration appears to be signatory
of the formation of self-assemblies. <sup>1</sup>H NMR resonances
of aggregating compounds were sensitive to the presence of a range
of molecular assemblies in solution including large molecular-size
entities, smaller multimers, and mixtures of assembled species. The
direct observation of aggregates via unusual NMR spectra also correlated
with promiscuous behavior of molecules in off-target in vitro pharmacology
assays. This empirical assay can have utility for predicting compound
promiscuity and should complement predictive methods that principally
rely on the computing of descriptors such as lipophilicity (cLogP)
and topological surface area (TPSA). This assay should serve as a
practical tool for medicinal chemists to monitor compound attributes
in aqueous solution and various pharmacologically relevant media,
as demonstrated herein