9EWU

Crystal structure of human butyrylcholinesterase in complex with (2R,3S)-1-[(cyclopropylmethyl)amino]-3-[(9H-fluoren-9-yl)amino]-4-phenylbutan-2-ol

This is a non-PDB format compatible entry.

Summary for 9EWU

• Entry DOI: 10.2210/pdb9ewu/pdb
• Descriptor: Cholinesterase, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]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: 63518.23

Authors

Panek, D.,Pasieka, A.,Malawska, B.,Nachon, F.,Brazzolotto, X. (deposition date: 2024-04-04, release date: 2025-02-05, Last modification date: 2025-02-12)

Primary citation

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.
Multifunctional, Fluorene-Based Modulator of Cholinergic and GABAergic Neurotransmission as a Novel Drug Candidate for Palliative Treatment of Alzheimer's Disease.
Angew.Chem.Int.Ed.Engl., 64:e202420510-e202420510, 2025

PubMed Abstract: Alzheimer'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 γ-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=0.21 μM) and GABA transporter 1 (IC=10.96 μM) and 3 (IC=7.76 μM), 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.

PubMed: 39523866
DOI: 10.1002/anie.202420510

Experimental method

X-RAY DIFFRACTION (2.45 Å)