Dual Reversible Coumarin Inhibitors Mutually Bound to Monoamine Oxidase B and Acetylcholinesterase Crystal Structures

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2022 Mar 18

PMID 35300078

Authors

Fredrik Ekstrom

Andrea Gottinger

Nina Forsgren

Marco Catto

Luca G Iacovino

Leonardo Pisani

Claudia Binda

Affiliations

Soon will be listed here.

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.

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