Ekström Fredrik, Gottinger Andrea, Forsgren Nina, Catto Marco, Iacovino Luca G, Pisani Leonardo, Binda Claudia
Swedish Defence Research Agency, CBRN Defence and Security, Umeå 901 82, Sweden.
Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy.
ACS Med Chem Lett. 2022 Feb 18;13(3):499-506. doi: 10.1021/acsmedchemlett.2c00001. eCollection 2022 Mar 10.
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.
多靶点导向配体（MTDLs）是应对多因素疾病复杂性的一个充满前景的前沿领域。单胺氧化酶B（MAO B）和乙酰胆碱酯酶（AChE）的协同抑制作用被认为在阿尔茨海默病的治疗中能产生增强效应。在先前报道的含香豆素的微摩尔或亚微摩尔双抑制剂中，化合物对MAO B表现出紧密结合抑制作用（ = 4.5 μM），且酶 值升高了5.5 °C。实际上，X射线晶体结构显示该化合物的结合在MAO B入口腔产生了意想不到的构象变化。有趣的是，该化合物与AChE酶峡谷具有很好的形状互补性，从催化阴离子亚位点（CAS）到外周阴离子亚位点（PAS）都深深嵌入其中，并在活性位点引起显著的结构变化。这些发现为双MAO B和AChE抑制剂的进一步开发提供了结构模板。
