Ekstrom_2022_ACS.Med.Chem.Lett_13_499

Reference

Title : Dual Reversible Coumarin Inhibitors Mutually Bound to Monoamine Oxidase B and Acetylcholinesterase Crystal Structures - Ekstrom_2022_ACS.Med.Chem.Lett_13_499
Author(s) : Ekstrom F , Gottinger A , Forsgren N , Catto M , Iacovino LG , Pisani P , Binda C
Ref : ACS Med Chem Lett , 13 :499 , 2022
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 1 returned a tight-binding inhibition of MAO B (Ki = 4.5 microM) and a +5.5 C increase in the enzyme Tm value. Indeed, the X-ray crystal structure revealed that binding of 1 produces unforeseen conformational changes at the MAO B entrance cavity. Interestingly, 1 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.

PubMedSearch : Ekstrom_2022_ACS.Med.Chem.Lett_13_499
PubMedID: 35300078
Gene_locus related to this paper: mouse-ACHE

Related information

Inhibitor 7QAK-Cpd1    7QB4-Cpd2
Gene_locus 7QAK-Cpd1    7QB4-Cpd2    mouse-ACHE
Structure 7QAK-Cpd1    7QB4-Cpd2    mouse-ACHE    7QAK    7QB4

Citations formats

Ekstrom F, Gottinger A, Forsgren N, Catto M, Iacovino LG, Pisani P, Binda C (2022)
Dual Reversible Coumarin Inhibitors Mutually Bound to Monoamine Oxidase B and Acetylcholinesterase Crystal Structures
ACS Med Chem Lett 13 :499

Ekstrom F, Gottinger A, Forsgren N, Catto M, Iacovino LG, Pisani P, Binda C (2022)
ACS Med Chem Lett 13 :499