9ewu
Crystal structure of human butyrylcholinesterase in complex with (2R,3S)-1-[(cyclopropylmethyl)amino]-3-[(9H-fluoren-9-yl)amino]-4-phenylbutan-2-ol
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 a neurodegenerative disorder characterized by memory loss and behavioral and psychological symptoms of dementia (BPSD). Given that cholinergic neurons are predominantly affected in AD, current treatments primarily aim to enhance cholinergic neurotransmission. However, imbalances in other neurotransmitters, such as gamma-aminobutyric acid (GABA), also contribute to AD symptomatology. In the presented research, using a combination of crystallography and computational methods we developed compound 6 as a dual modulator of GABAergic and cholinergic neurotransmission systems. Compound 6 demonstrated inhibition of BuChE (IC(50)=0.21 muM) and GABA transporter 1 (IC(50)=10.96 muM) and 3 (IC(50)=7.76 muM), along with a favorable drug-likeness profile. Subsequent in vivo studies revealed the effectiveness of 6 in enhancing memory retention and alleviating anxiety and depression symptoms in animal models, while also proving safe and bioavailable for oral administration. The innovative multi-target-directed ligand 6 offers a new approach to treating cognitive deficits and BPSD in AD. Multifunctional, Fluorene-Based Modulator of Cholinergic and GABAergic Neurotransmission as a Novel Drug Candidate for Palliative Treatment of Alzheimer's Disease.,Panek D, Pasieka A, Jonczyk J, Gawlinska M, Zareba P, Siwek A, Wolak M, Mordyl B, Gluch-Lutwin M, Latacz G, Brazzolotto X, Chantegreil F, Nachon F, Zdarova Karasova J, Pejchal J, Mzik M, Sestak V, Prchal L, Odvarkova J, Soukup O, Korabecny J, Sorf A, Hamsikova M, Zemanova L, Muckova L, Vanova N, Dryja P, Salat K, Hofner G, Wanner K, Wieckowska A, Malawska B Angew Chem Int Ed Engl. 2024 Nov 11:e202420510. doi: 10.1002/anie.202420510. PMID:39523866[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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