Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B Inhibitors

A series of dietary flavonoid acacetin 7-O-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 1c, 2c, 3c, a...

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Autores principales: Gogineni, Vedanjali, Nael, Manal A., Chaurasiya, Narayan D., Elokely, Khaled M., McCurdy, Christopher R., Rimoldi, John M., Cutler, Stephen J., Tekwani, Babu L., León, Francisco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533211/
https://www.ncbi.nlm.nih.gov/pubmed/34680421
http://dx.doi.org/10.3390/biomedicines9101304
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author Gogineni, Vedanjali
Nael, Manal A.
Chaurasiya, Narayan D.
Elokely, Khaled M.
McCurdy, Christopher R.
Rimoldi, John M.
Cutler, Stephen J.
Tekwani, Babu L.
León, Francisco
author_facet Gogineni, Vedanjali
Nael, Manal A.
Chaurasiya, Narayan D.
Elokely, Khaled M.
McCurdy, Christopher R.
Rimoldi, John M.
Cutler, Stephen J.
Tekwani, Babu L.
León, Francisco
author_sort Gogineni, Vedanjali
collection PubMed
description A series of dietary flavonoid acacetin 7-O-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 1c, 2c, 3c, and 4c were the most potent with a Ki of 37 to 68 nM against MAO-B. Compounds 1c–4c displayed more than a thousand-fold selectivity index towards MAO-B compared with MAO-A. Moreover, compounds 1c and 2c 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.
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spelling pubmed-85332112021-10-23 Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B Inhibitors Gogineni, Vedanjali Nael, Manal A. Chaurasiya, Narayan D. Elokely, Khaled M. McCurdy, Christopher R. Rimoldi, John M. Cutler, Stephen J. Tekwani, Babu L. León, Francisco Biomedicines Article A series of dietary flavonoid acacetin 7-O-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 1c, 2c, 3c, and 4c were the most potent with a Ki of 37 to 68 nM against MAO-B. Compounds 1c–4c displayed more than a thousand-fold selectivity index towards MAO-B compared with MAO-A. Moreover, compounds 1c and 2c 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. MDPI 2021-09-24 /pmc/articles/PMC8533211/ /pubmed/34680421 http://dx.doi.org/10.3390/biomedicines9101304 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Gogineni, Vedanjali
Nael, Manal A.
Chaurasiya, Narayan D.
Elokely, Khaled M.
McCurdy, Christopher R.
Rimoldi, John M.
Cutler, Stephen J.
Tekwani, Babu L.
León, Francisco
Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B Inhibitors
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533211/
https://www.ncbi.nlm.nih.gov/pubmed/34680421
http://dx.doi.org/10.3390/biomedicines9101304
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