Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B Inhibitors
A series of dietary flavonoid acacetin 7-<i>O</i>-methyl ether derivatives were computationally designed aiming to improve the selectivity and potency profiles against monoamine oxidase (MAO) B. The designed compounds were evaluated for their potential to inhibit human MAO-A and -B. Comp...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-09-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/9/10/1304 |
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| author | Vedanjali Gogineni Manal A. Nael Narayan D. Chaurasiya Khaled M. Elokely Christopher R. McCurdy John M. Rimoldi Stephen J. Cutler Babu L. Tekwani Francisco León |
| author_facet | Vedanjali Gogineni Manal A. Nael Narayan D. Chaurasiya Khaled M. Elokely Christopher R. McCurdy John M. Rimoldi Stephen J. Cutler Babu L. Tekwani Francisco León |
| author_sort | Vedanjali Gogineni |
| collection | DOAJ |
| description | A series of dietary flavonoid acacetin 7-<i>O</i>-methyl ether derivatives were computationally designed aiming to improve the selectivity and potency profiles against monoamine oxidase (MAO) B. The designed compounds were evaluated for their potential to inhibit human MAO-A and -B. Compounds <b>1c</b>, <b>2c</b>, <b>3c</b>, and <b>4c</b> were the most potent with a Ki of 37 to 68 nM against MAO-B. Compounds <b>1c</b>–<b>4c</b> displayed more than a thousand-fold selectivity index towards MAO-B compared with MAO-A. Moreover, compounds <b>1c</b> and <b>2c</b> showed reversible inhibition of MAO-B. These results provide a basis for further studies on the potential application of these modified flavonoids for the treatment of Parkinson’s Disease and other neurological disorders. |
| first_indexed | 2024-03-10T06:43:56Z |
| format | Article |
| id | doaj.art-fd228e079fe141d79d024b929fa59584 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T06:43:56Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-fd228e079fe141d79d024b929fa595842023-11-22T17:29:45ZengMDPI AGBiomedicines2227-90592021-09-01910130410.3390/biomedicines9101304Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B InhibitorsVedanjali Gogineni0Manal A. Nael1Narayan D. Chaurasiya2Khaled M. Elokely3Christopher R. McCurdy4John M. Rimoldi5Stephen J. Cutler6Babu L. Tekwani7Francisco León8Department of BioMolecular Sciences, Division of Medicinal Chemistry, University of Mississippi, Oxford, MS 38677, USADepartment of Chemistry, Institute for Computational Molecular Science, Temple University, Philadelphia, PA 19122, USADivision of Drug Discovery, Southern Research, Birmingham, AL 35205, USADepartment of Chemistry, Institute for Computational Molecular Science, Temple University, Philadelphia, PA 19122, USADepartment of BioMolecular Sciences, Division of Medicinal Chemistry, University of Mississippi, Oxford, MS 38677, USADepartment of BioMolecular Sciences, Division of Medicinal Chemistry, University of Mississippi, Oxford, MS 38677, USADepartment of BioMolecular Sciences, Division of Medicinal Chemistry, University of Mississippi, Oxford, MS 38677, USADivision of Drug Discovery, Southern Research, Birmingham, AL 35205, USADepartment of BioMolecular Sciences, Division of Medicinal Chemistry, University of Mississippi, Oxford, MS 38677, USAA series of dietary flavonoid acacetin 7-<i>O</i>-methyl ether derivatives were computationally designed aiming to improve the selectivity and potency profiles against monoamine oxidase (MAO) B. The designed compounds were evaluated for their potential to inhibit human MAO-A and -B. Compounds <b>1c</b>, <b>2c</b>, <b>3c</b>, and <b>4c</b> were the most potent with a Ki of 37 to 68 nM against MAO-B. Compounds <b>1c</b>–<b>4c</b> displayed more than a thousand-fold selectivity index towards MAO-B compared with MAO-A. Moreover, compounds <b>1c</b> and <b>2c</b> showed reversible inhibition of MAO-B. These results provide a basis for further studies on the potential application of these modified flavonoids for the treatment of Parkinson’s Disease and other neurological disorders.https://www.mdpi.com/2227-9059/9/10/1304flavonoidsParkinson’s Diseasemonoamine oxidases A and Bacacetindocking |
| spellingShingle | Vedanjali Gogineni Manal A. Nael Narayan D. Chaurasiya Khaled M. Elokely Christopher R. McCurdy John M. Rimoldi Stephen J. Cutler Babu L. Tekwani Francisco León Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B Inhibitors Biomedicines flavonoids Parkinson’s Disease monoamine oxidases A and B acacetin docking |
| title | Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B Inhibitors |
| title_full | Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B Inhibitors |
| title_fullStr | Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B Inhibitors |
| title_full_unstemmed | Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B Inhibitors |
| title_short | Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B Inhibitors |
| title_sort | computationally assisted lead optimization of novel potent and selective mao b inhibitors |
| topic | flavonoids Parkinson’s Disease monoamine oxidases A and B acacetin docking |
| url | https://www.mdpi.com/2227-9059/9/10/1304 |
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