Structure Report for: 7QB4

Fredrik Ekstrom, Andrea Gottinger, Nina Forsgren, Marco Catto, Luca G. Iacovino, Leonardo Pisani, and Claudia Binda

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


ESTHER: Ekstrom_2022_ACS.Med.Chem.Lett_13_499
PubMedSearch: Ekstrom 2022 ACS.Med.Chem.Lett 13 499
PubMedID: 35300078
Gene_locus related to this paper: mouse-ACHE
Inhibitor(s) related to this paper: 7QAK-Cpd1, 7QB4-Cpd2

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.