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 rela...
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MDPI AG
2020-12-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/24/5962 |
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doaj-80fff5dcb5e043d7843bda38e2c268322020-12-17T00:04:10ZengMDPI AGMolecules1420-30492020-12-01255962596210.3390/molecules25245962How to Separate Kinase Inhibition from Undesired Monoamine Oxidase A Inhibition—The Development of the DYRK1A Inhibitor AnnH75 from the Alkaloid HarmineAnne Wurzlbauer0Katharina Rüben1Ece Gürdal2Apirat Chaikuad3Stefan Knapp4Wolfgang Sippl5Walter Becker6Franz Bracher7Department of Pharmacy–Center for Drug Research, Ludwig-Maximilians University, 81377 Munich, GermanyInstitute of Pharmacology and Toxicology, RWTH Aachen University, 52074 Aachen, GermanyInstitute of Pharmacy, Martin Luther University Halle-Wittenberg, 06120 Halle, GermanyInstitute of Pharmaceutical Chemistry and Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences (BMLS), Goethe-University Frankfurt, 60438 Frankfurt, GermanyInstitute of Pharmaceutical Chemistry and Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences (BMLS), Goethe-University Frankfurt, 60438 Frankfurt, GermanyInstitute of Pharmacy, Martin Luther University Halle-Wittenberg, 06120 Halle, GermanyInstitute of Pharmacology and Toxicology, RWTH Aachen University, 52074 Aachen, GermanyDepartment of Pharmacy–Center for Drug Research, Ludwig-Maximilians University, 81377 Munich, GermanyThe 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 <b>AnnH75</b> 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.https://www.mdpi.com/1420-3049/25/24/5962alkaloidharmineDYRK1Amonoamine oxidase Adocking studiesco-crystallization |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Anne Wurzlbauer Katharina Rüben Ece Gürdal Apirat Chaikuad Stefan Knapp Wolfgang Sippl Walter Becker Franz Bracher |
| spellingShingle |
Anne Wurzlbauer Katharina Rüben Ece Gürdal Apirat Chaikuad Stefan Knapp Wolfgang Sippl Walter Becker Franz Bracher How to Separate Kinase Inhibition from Undesired Monoamine Oxidase A Inhibition—The Development of the DYRK1A Inhibitor AnnH75 from the Alkaloid Harmine Molecules alkaloid harmine DYRK1A monoamine oxidase A docking studies co-crystallization |
| author_facet |
Anne Wurzlbauer Katharina Rüben Ece Gürdal Apirat Chaikuad Stefan Knapp Wolfgang Sippl Walter Becker Franz Bracher |
| author_sort |
Anne Wurzlbauer |
| title |
How to Separate Kinase Inhibition from Undesired Monoamine Oxidase A Inhibition—The Development of the DYRK1A Inhibitor AnnH75 from the Alkaloid Harmine |
| title_short |
How to Separate Kinase Inhibition from Undesired Monoamine Oxidase A Inhibition—The Development of the DYRK1A Inhibitor AnnH75 from the Alkaloid Harmine |
| title_full |
How to Separate Kinase Inhibition from Undesired Monoamine Oxidase A Inhibition—The Development of the DYRK1A Inhibitor AnnH75 from the Alkaloid Harmine |
| title_fullStr |
How to Separate Kinase Inhibition from Undesired Monoamine Oxidase A Inhibition—The Development of the DYRK1A Inhibitor AnnH75 from the Alkaloid Harmine |
| title_full_unstemmed |
How to Separate Kinase Inhibition from Undesired Monoamine Oxidase A Inhibition—The Development of the DYRK1A Inhibitor AnnH75 from the Alkaloid Harmine |
| title_sort |
how to separate kinase inhibition from undesired monoamine oxidase a inhibition—the development of the dyrk1a inhibitor annh75 from the alkaloid harmine |
| publisher |
MDPI AG |
| series |
Molecules |
| issn |
1420-3049 |
| publishDate |
2020-12-01 |
| description |
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 <b>AnnH75</b> 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. |
| topic |
alkaloid harmine DYRK1A monoamine oxidase A docking studies co-crystallization |
| url |
https://www.mdpi.com/1420-3049/25/24/5962 |
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