5dyy
From Proteopedia
Crystal structure of human butyrylcholinesterase in complex with N-((1-benzylpiperidin-3-yl)methyl)naphthalene-2-sulfonamide
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 PubMedAlzheimer's disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with the disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. Potent, selective and reversible human BChE inhibitors were developed. The solved crystal structure of human BChE in complex with the most potent inhibitor reveals its binding mode and provides the molecular basis of its low nanomolar potency. Additionally, this compound is noncytotoxic and has neuroprotective properties. Furthermore, this inhibitor moderately crosses the blood-brain barrier and improves memory, cognitive functions and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic adverse effects. Our study provides an advanced lead compound for developing drugs for alleviating symptoms caused by cholinergic hypofunction in advanced AD. Development of an in-vivo active reversible butyrylcholinesterase inhibitor.,Kosak U, Brus B, Knez D, Sink R, Zakelj S, Trontelj J, Pislar A, Slenc J, Gobec M, Zivin M, Tratnjek L, Perse M, Salat K, Podkowa A, Filipek B, Nachon F, Brazzolotto X, Wieckowska A, Malawska B, Stojan J, Rascan IM, Kos J, Coquelle N, Colletier JP, Gobec S Sci Rep. 2016 Dec 21;6:39495. doi: 10.1038/srep39495. PMID:28000737[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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