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