DMSO: A Mixed-Competitive Inhibitor of Human Acetylcholinesterase

• Published in: ACS chemical neuroscience Vol. 8; no. 12; pp. 2618 - 2625
• Main Authors: Kumar, Amit, Darreh-Shori, Taher
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 20-12-2017
• Subjects: Acetylcholinesterase - chemistry; Binding Sites; Cholinesterase Inhibitors - chemistry; Dimethyl Sulfoxide - chemistry; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Stability; Humans; Medicin och hälsovetenskap; Models, Chemical; Protein Binding; Solvents - chemistry; Substrate Specificity; Dimethyl sulfoxide (DMSO); organic solvents; Alzheimer’s disease (AD); acetylcholinesterase (AChE); drug discovery and development; enzyme kinetics
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.7b00344

Dimethyl sulfoxide (DMSO) is the most common organic solvent used in biochemical and cellular assays during drug discovery programs. Despite its wide use, the effect of DMSO on several enzyme classes, which are crucial targets of the new therapeutic agents, are still unexplored. Here, we report the detailed biochemical analysis of the effects of DMSO on the human acetylcholine-degrading enzyme, acetylcholinesterase (AChE), the primary target of current Alzheimer’s therapeutics. Our analysis showed that DMSO is a considerably potent and highly selective irreversible mixed-competitive inhibitor of human AChE with IC50 values in the lower millimolar range, corresponding to 0.88% to 2.6% DMSO (v/v). Most importantly, 1–4% (v/v) DMSO, the commonly used experimental concentrations, showed ∼37–80% inhibition of human AChE activity. We believe that our results will assist in developing stringent protocols and help in the better interpretation of experimental outcomes during screening and biological evaluation of new drugs.