targeting acetylcholinesterase identification of chemical leads by high throughput screening, structure determination and molecular modeling针对乙酰胆碱酯酶识别化学带来的高通量筛选、结构测定和分子建模.pdf

Targeting Acetylcholinesterase: Identification of Chemical Leads by High Throughput Screening, Structure Determination and Molecular Modeling 1 1 2 ¨ 2 2 Lotta Berg , C. David Andersson , Elisabet Artursson , Andreas Hornberg , Anna-Karin Tunemalm , 1 ¨ 2 Anna Linusson *, Fredrik Ekstrom * ˚ ˚ ˚ 1 Department of Chemistry, Umea University, Umea, Sweden, 2 Swedish Defence Research Agency, CBRN Defence and Security, Umea, Sweden Abstract Acetylcholinesterase (AChE) is an essential enzyme that terminates cholinergic transmission by rapid hydrolysis of the neurotransmitter acetylcholine. Compounds inhibiting this enzyme can be used (inter alia) to treat cholinergic deficiencies (e.g. in Alzheimer’s disease), but may also act as dangerous toxins (e.g. nerve agents such as sarin). Treatment of nerve agent poisoning involves use of antidotes, small molecules capable of reactivating AChE. We have screened a collection of organic molecules to assess their ability to inhibit the enzymatic activity of AChE, aiming to find lead compounds for further optimization leading to drugs with increased efficacy and/or decreased side effects. 124 inhibitors were discovered, with considerable chemical diversity regarding size, polarity, flexibility and charge distribution. An extensive structure determination campaign resulted in a set of crystal structures of protein-ligand complexes. Overall, the ligands have substantial interac