title: Suppression of problematic compound oligomerization by cosolubilization of nondetergent sulfobetaines.
abstract: Numerous small organic compounds exist in equilibrium among monomers, soluble oligomers, and insoluble aggregates in aqueous solution. Compound aggregation is a major reason for false positives in drug screening, and even soluble oligomers can interfere with structural and biochemical analyses. However, an efficient way to manage the equilibrium of aggregation-prone compounds, especially those involved with soluble oligomers, has not been established. In this study, solution NMR spectroscopy was used as a suitable technique to detect compound oligomers in equilibrium, and it was demonstrated that cosolubilization of nondetergent sulfobetaines (NDSBs) can largely suppress compound oligomerization and aggregation by shifting the equilibrium toward the monomers. The rotational correlation time was obtained from the ratio of the selective and nonselective longitudinal NMR relaxation times, which directly and quantitatively reflected the apparent sizes of the compounds in the equilibrium. The rotational correlation time of the aggregation-prone compound SKF86002 (1 mM) was substantially reduced from 0.31 to 0.23 ns by cosolubilization of 100 mM NDSB195. NDSB cosolubilization allowed us to perform successful structural and biochemical experiments with substantially fewer artifacts, which represents a strategy to directly resolve the problematic oligomerization and aggregation of compounds.
authors.affiliation: Biomedicinal Information Research Center (BIRC) and Molecular Profiling Research Center (Molprof), National Institute of Advanced Industrial Science and Technology (AIST), 2-3-26 Aomi, Koto-ku, Tokyo 135-0064 (Japan); Japan Biological Informatics Consortium (JBIC), 2-3-26 Aomi, Koto-ku, Tokyo 135-0064 (Japan).
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Mizukoshi
authors.forename: Koh
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Misa
authors.initials: M
authors.lastname: Arutaki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takizawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hanzawa
authors.forename: Hideo
authors.initials: H
authors.lastname: Takahashi
authors.forename: Ichio
authors.initials: I
authors.lastname: Shimada
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D001622:Betaine / Q000031:analogs & derivatives* / Q000737:chemistry; D055808:Drug Discovery; D007093:Imidazoles / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D012995:Solubility; D012996:Solutions; D013844:Thiazoles / Q000737:chemistry*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007093:Imidazoles; C111794:NDSB 195; D012996:Solutions; D013844:Thiazoles; D001622:Betaine; C483727:sulfobetaine; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole
keywords: NMR spectroscopy; artifacts; drug discovery; nondetergent sulfobetaines; oligomerization