7QB4

Mus Musculus Acetylcholinesterase in complex with 7-[(1-benzylpiperidin-3-yl)methoxy]-3,4-dimethyl-2H-chromen-2-one

Summary for 7QB4

• Entry DOI: 10.2210/pdb7qb4/pdb
• Descriptor: Acetylcholinesterase, 2-acetamido-2-deoxy-beta-D-glucopyranose, 3,4-dimethyl-7-[[1-(phenylmethyl)piperidin-4-yl]methoxy]chromen-2-one, ... (8 entities in total)
• Functional Keywords: inhibitor, complex, hydrolase
• Biological source: Mus musculus (House mouse)
• Total number of polymer chains: 2
• Total formula weight: 123440.57

Authors

Ekstrom, F.J.,Forsgren, N. (deposition date: 2021-11-18, release date: 2022-04-06, Last modification date: 2024-10-23)

Primary citation

Ekstrom, F.,Gottinger, A.,Forsgren, N.,Catto, M.,Iacovino, L.G.,Pisani, L.,Binda, C.
Dual Reversible Coumarin Inhibitors Mutually Bound to Monoamine Oxidase B and Acetylcholinesterase Crystal Structures.
Acs Med.Chem.Lett., 13:499-506, 2022

PubMed Abstract: Multitarget directed ligands (MTDLs) represent a promising frontier in tackling the complexity of multifactorial pathologies. The synergistic inhibition of monoamine oxidase B (MAO B) and acetylcholinesterase (AChE) is believed to provide a potentiated effect in the treatment of Alzheimer's disease. Among previously reported micromolar or sub-micromolar coumarin-bearing dual inhibitors, compound returned a tight-binding inhibition of MAO B ( = 4.5 μM) and a +5.5 °C increase in the enzyme value. Indeed, the X-ray crystal structure revealed that binding of produces unforeseen conformational changes at the MAO B entrance cavity. Interestingly, showed great shape complementarity with the AChE enzymatic gorge, being deeply buried from the catalytic anionic subsite (CAS) to the peripheral anionic subsite (PAS) and causing significant structural changes in the active site. These findings provide structural templates for further development of dual MAO B and AChE inhibitors.

PubMed: 35300078
DOI: 10.1021/acsmedchemlett.2c00001

Experimental method

X-RAY DIFFRACTION (2.50001104077 Å)