9I02

Structure of recombinant human butyrylcholinesterase in complex with (S)-N-((1-benzylpyrrolidin-3-yl)methyl)-N-methylnaphthalene-2-sulfonamide

This is a non-PDB format compatible entry.

Summary for 9I02

• Entry DOI: 10.2210/pdb9i02/pdb
• Descriptor: Cholinesterase, SULFATE ION, CHLORIDE ION, ... (12 entities in total)
• Functional Keywords: butyrylcholinesterase, inhibitor, complex, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 64123.65

Authors

Brazzolotto, X.,Kosak, U.,Gobec, S.,Nachon, F. (deposition date: 2025-01-14, release date: 2025-07-02)

Primary citation

Kosak, U.,Strasek Benedik, N.,Knez, D.,Zakelj, S.,Trontelj, J.,Pislar, A.,Horvat, S.,Bolje, A.,Znidarsic, N.,Grgurevic, N.,Svara, T.,Kljun, J.,Skrzypczak-Wiercioch, A.,Lv, B.,Xiong, Y.,Wang, Q.,Bian, R.,Shao, J.,Dias, J.,Nachon, F.,Brazzolotto, X.,Stojan, J.,Sun, H.,Salat, K.,Gobec, S.
Lead Optimization of a Butyrylcholinesterase Inhibitor for the Treatment of Alzheimer's Disease.
J.Med.Chem., 68:11693-11723, 2025

PubMed Abstract: Butyrylcholinesterase (BChE) is a promising drug target for alleviating the symptoms of canine cognitive dysfunction (CCD) and Alzheimer's disease (AD). We have recently developed lead compound , a racemic, nanomolar BChE inhibitor with procognitive effects in mice with scopolamine-induced AD-like symptoms and dogs suffering from CCD. To overcome its modest brain exposure, we developed compound , a more potent BChE inhibitor with a 7-fold higher in vivo brain exposure. It has procognitive effects in mice with scopolamine-induced AD-like symptoms and, superior to compound , also in mice with Aβ-induced AD-like symptoms. Compound produces no cholinergic adverse effects or motor deficits and has no acute toxic effects in mice. This makes sulfonamide an optimized lead compound for alleviating the symptoms of AD.

PubMed: 40454648
DOI: 10.1021/acs.jmedchem.5c00577

Experimental method

X-RAY DIFFRACTION (2.58 Å)