title: Monitoring drug self-aggregation and potential for promiscuity in off-target in vitro pharmacology screens by a practical NMR strategy.
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. (1)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.
authors.affiliation: Department of Chemistry, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Quebec, H7S 2G5, Canada.
authors.forename: Steven R
authors.initials: SR
authors.lastname: LaPlante
authors.forename: Norman
authors.initials: N
authors.lastname: Aubry
authors.forename: Gordon
authors.initials: G
authors.lastname: Bolger
authors.forename: Pierre
authors.initials: P
authors.lastname: Bonneau
authors.forename: Rebekah
authors.initials: R
authors.lastname: Carson
authors.forename: René
authors.initials: R
authors.lastname: Coulombe
authors.forename: Claudio
authors.initials: C
authors.lastname: Sturino
authors.forename: Pierre L
authors.initials: PL
authors.lastname: Beaulieu
mesh_terms: D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D015335:Molecular Probes
chemical_list: D015335:Molecular Probes