7q1m | pdb_00007q1m
Crystal structure of human butyrylcholinesterase in complex with N-[(2S)-3-[(cyclohexylmethyl)amino]-2-hydroxypropyl]-2,2-diphenylacetamide
Structural highlights
DiseaseCHLE_HUMAN Defects in BCHE are the cause of butyrylcholinesterase deficiency (BChE deficiency) [MIM:177400. BChE deficiency is a metabolic disorder characterized by prolonged apnoea after the use of certain anesthetic drugs, including the muscle relaxants succinylcholine or mivacurium and other ester local anesthetics. The duration of the prolonged apnoea varies significantly depending on the extent of the enzyme deficiency. BChE deficiency is a multifactorial disorder. The hereditary condition is transmitted as an autosomal recessive trait. FunctionCHLE_HUMAN Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.[1] [2] Publication Abstract from PubMedThe 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(50) = 40 nM) with selectivity over AChE and relevant off-targets, including H(1), M(1), alpha(1A) and beta(1) 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(50) = 2.85 muM) and hERG inhibition (less than 50% at 10 muM). 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. Discovery of new, highly potent and selective inhibitors of BuChE - design, synthesis, in vitro and in vivo evaluation and crystallography studies.,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 Eur J Med Chem. 2023 Mar 5;249:115135. doi: 10.1016/j.ejmech.2023.115135. Epub , 2023 Jan 18. PMID:36696766[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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