7Q1O

Crystal structure of human butyrylcholinesterase in complex with N-[(2S)-3-[(cyclohexylmethyl)amino]-2-hydroxypropyl]-3,3-diphenylpropanamide

Summary for 7Q1O

• Entry DOI: 10.2210/pdb7q1o/pdb
• Descriptor: Cholinesterase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• Functional Keywords: butyrylcholinesterase, inhibitor, complex, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 63470.47

Authors

Brazzolotto, X.,Panek, D.,Pasieka, A.,Malawska, B.,Nachon, F. (deposition date: 2021-10-20, release date: 2022-11-16, Last modification date: 2024-02-07)

Primary citation

Panek, D.,Pasieka, A.,Latacz, G.,Zareba, P.,Szczech, M.,Godyn, J.,Chantegreil, F.,Nachon, F.,Brazzolotto, X.,Skrzypczak-Wiercioch, A.,Walczak, M.,Smolik, M.,Salat, K.,Hofner, G.,Wanner, K.,Wieckowska, A.,Malawska, B.
Discovery of new, highly potent and selective inhibitors of BuChE - design, synthesis, in vitro and in vivo evaluation and crystallography studies.
Eur.J.Med.Chem., 249:115135-115135, 2023

PubMed Abstract: The symptomatic and disease-modifying effects of butyrylcholinesterase (BuChE) inhibitors provide an encouraging premise for researching effective treatments for Alzheimer's disease. Here, we examined a series of compounds with a new chemical scaffold based on 3-(cyclohexylmethyl)amino-2-hydroxypropyl, and we identified a highly selective hBuChE inhibitor (29). Based on extensive in vitro and in vivo evaluations of the compound and its enantiomers, (R)-29 was identified as a promising candidate for further development. Compound (R)-29 is a potent hBuChE inhibitor (IC = 40 nM) with selectivity over AChE and relevant off-targets, including H, M, α and β receptors. The compound displays high metabolic stability on human liver microsomes (90% of the parent compound after 2 h of incubation), and its safety was confirmed through examining the cytotoxicity on the HepG2 cell line (LC = 2.85 μM) and hERG inhibition (less than 50% at 10 μM). While (rac)-29 lacked an effect in vivo and showed limited penetration to the CNS in pharmacokinetics studies, compound (R)-29 exhibited a procognitive effect at 15 mg/kg in the passive avoidance task in scopolamine-treated mice.

PubMed: 36696766
DOI: 10.1016/j.ejmech.2023.115135

Experimental method

X-RAY DIFFRACTION (2.65 Å)