How to separate kinase inhibition from undesired monoamine oxidase a inhibition - the development of the DYRK1A inhibitor AnnH75 from the alkaloid harmine
- The β-carboline alkaloid harmine is a potent DYRK1A inhibitor, but suffers from undesired potent inhibition of MAO-A, which strongly limits its application. We synthesized more than 60 analogues of harmine, either by direct modification of the alkaloid or by de novo synthesis of β-carboline and related scaffolds aimed at learning about structure-activity relationships for inhibition of both DYRK1A and MAO-A, with the ultimate goal of separating desired DYRK1A inhibition from undesired MAO-A inhibition. Based on evidence from published crystal structures of harmine bound to each of these enzymes, we performed systematic structure modifications of harmine yielding DYRK1A-selective inhibitors characterized by small polar substituents at N-9 (which preserve DYRK1A inhibition and eliminate MAO-A inhibition) and beneficial residues at C-1 (methyl or chlorine). The top compound AnnH75 remains a potent DYRK1A inhibitor, and it is devoid of MAO-A inhibition. Its binding mode to DYRK1A was elucidated by crystal structure analysis, and docking experiments provided additional insights for this attractive series of DYRK1A and MAO-A inhibitors.
Author: | Anne Wurzlbauer, Katharina Rüben, Ece Gürdal, Apirat ChaikuadORCiD, Stefan KnappORCiDGND, Wolfgang Sippl, Walter Becker, Franz BracherORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-574774 |
DOI: | https://doi.org/10.3390/molecules25245962 |
ISSN: | 1420-3049 |
Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/33339338 |
Parent Title (English): | Molecules |
Publisher: | MDPI |
Place of publication: | Basel |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2020/12/16 |
Date of first Publication: | 2020/12/16 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2020/12/27 |
Tag: | DYRK1A; alkaloid; co-crystallization; docking studies; harmine; monoamine oxidase A; structure–activity relationships |
Volume: | 25 |
Issue: | Article 5962 |
Page Number: | 34 |
HeBIS-PPN: | 477814018 |
Institutes: | Biowissenschaften / Biowissenschaften |
Medizin / Medizin | |
Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit | |
Sammlungen: | Universitätspublikationen |
Licence (German): | Creative Commons - Namensnennung 4.0 |