Monitoring Drug Self-Aggregation and Potential for Promiscuity in Off-Target In Vitro Pharmacology Screens by a Practical NMR Strategy

详细信息    查看全文

• 作者：Steven R. LaPlante ; Norman Aubry ; Gordon Bolger ; Pierre Bonneau ; Rebekah Carson ; Ren茅 Coulombe ; Claudio Sturino ; Pierre L. Beaulieu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September 12, 2013
• 年：2013
• 卷：56
• 期：17
• 页码：7073-7083
• 全文大小：634K
• 年卷期：v.56,no.17(September 12, 2013)
• ISSN：1520-4804

文摘

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. ¹H 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.