4A23

Mus musculus Acetylcholinesterase in complex with racemic C5685

Summary for 4A23

• Entry DOI: 10.2210/pdb4a23/pdb
• Related: 1C2B 1C2O 1J06 1J07 1KU6 1MAA 1MAH 1N5M 1N5R 1Q83 1Q84 2C0P 2C0Q 2H9Y 2HA0 2HA2 2HA3 2HA4 2HA5 2HA6 2HA7 2JEY 2JEZ 2JF0 2JGE 2JGF 2JGG 2JGH 2JGI 2JGJ 2JGK 2JGL 2JGM 2WHP 2WHQ 2WHR 2WLS 2WU3 2WU4 2XUD 2XUF 2XUG 2XUH 2XUI 2XUJ 2XUK 2XUO 2XUP 2XUQ 2Y2U 2Y2V 4A16
• Descriptor: ACETYLCHOLINESTERASE, 4-(DIMETHYLAMINO)-N-{[(2R)-1-ETHYLPYRROLIDIN-2-YL]METHYL}-2-METHOXY-5-NITROBENZAMIDE, 4-(DIMETHYLAMINO)-N-{[(2S)-1-ETHYLPYRROLIDIN-2-YL]METHYL}-2-METHOXY-5-NITROBENZAMIDE, ... (6 entities in total)
• Functional Keywords: hydrolase, cholinesterase
• Biological source: MUS MUSCULUS (HOUSE MOUSE)
• Total number of polymer chains: 2
• Total formula weight: 122754.66

Authors

Berg, L.,Andersson, C.D.,Artrursson, E.,Hornberg, A.,Tunemalm, A.K.,Linusson, A.,Ekstrom, F. (deposition date: 2011-09-22, release date: 2011-12-07, Last modification date: 2024-11-13)

Primary citation

Berg, L.,Andersson, C.D.,Artursson, E.,Hornberg, A.,Tunemalm, A.K.,Linusson, A.,Ekstrom, F.
Targeting Acetylcholinesterase: Identification of Chemical Leads by High Throughput Screening, Structure Determination and Molecular Modeling.
Plos One, 6:26039-, 2011

PubMed 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 interactions with the peripheral anionic site of AChE, and the majority form additional interactions with the catalytic site (CAS). Reproduction of the bioactive conformation of six of the ligands using molecular docking simulations required modification of the default parameter settings of the docking software. The results show that docking-assisted structure-based design of AChE inhibitors is challenging and requires crystallographic support to obtain reliable results, at least with currently available software. The complex formed between C5685 and Mus musculus AChE (C5685•mAChE) is a representative structure for the general binding mode of the determined structures. The CAS binding part of C5685 could not be structurally determined due to a disordered electron density map and the developed docking protocol was used to predict the binding modes of this part of the molecule. We believe that chemical modifications of our discovered inhibitors, biochemical and biophysical characterization, crystallography and computational chemistry provide a route to novel AChE inhibitors and reactivators.

PubMed: 22140425
DOI: 10.1371/JOURNAL.PONE.0026039

Experimental method

X-RAY DIFFRACTION (2.4 Å)