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

doi:10.3390/biomedicines9101304

Open AccessArticle

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

by

Vedanjali Gogineni

^1,2,

Manal A. Nael

^3,4,†,

Narayan D. Chaurasiya

^5,6,†,

Khaled M. Elokely

^3,4

,

Christopher R. McCurdy

^1,7,

John M. Rimoldi

¹,

Stephen J. Cutler

^1,8,

Babu L. Tekwani

^5,6,*

and

Francisco León

^1,8,*

¹

Department of BioMolecular Sciences, Division of Medicinal Chemistry, University of Mississippi, Oxford, MS 38677, USA

²

Department of Drug Discovery, Biomedical Sciences and Public Health, College of Pharmacy, Medical University of South Carolina, Charleston, SC 29425, USA

³

Department of Chemistry, Institute for Computational Molecular Science, Temple University, Philadelphia, PA 19122, USA

⁴

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt

⁵

Division of Drug Discovery, Southern Research, Birmingham, AL 35205, USA

⁶

National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, Oxford, MS 38677, USA

⁷

Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA

⁸

Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this study.

Biomedicines 2021, 9(10), 1304; https://doi.org/10.3390/biomedicines9101304

Submission received: 9 August 2021 / Revised: 10 September 2021 / Accepted: 18 September 2021 / Published: 24 September 2021

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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Abstract

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.

Keywords: flavonoids; Parkinson’s Disease; monoamine oxidases A and B; acacetin; docking

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MDPI and ACS Style

Gogineni, V.; Nael, M.A.; Chaurasiya, N.D.; Elokely, K.M.; McCurdy, C.R.; Rimoldi, J.M.; Cutler, S.J.; Tekwani, B.L.; León, F. Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B Inhibitors. Biomedicines 2021, 9, 1304. https://doi.org/10.3390/biomedicines9101304

AMA Style

Gogineni V, Nael MA, Chaurasiya ND, Elokely KM, McCurdy CR, Rimoldi JM, Cutler SJ, Tekwani BL, León F. Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B Inhibitors. Biomedicines. 2021; 9(10):1304. https://doi.org/10.3390/biomedicines9101304

Chicago/Turabian Style

Gogineni, Vedanjali, Manal A. Nael, Narayan D. Chaurasiya, Khaled M. Elokely, Christopher R. McCurdy, John M. Rimoldi, Stephen J. Cutler, Babu L. Tekwani, and Francisco León. 2021. "Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B Inhibitors" Biomedicines 9, no. 10: 1304. https://doi.org/10.3390/biomedicines9101304

APA Style

Gogineni, V., Nael, M. A., Chaurasiya, N. D., Elokely, K. M., McCurdy, C. R., Rimoldi, J. M., Cutler, S. J., Tekwani, B. L., & León, F. (2021). Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B Inhibitors. Biomedicines, 9(10), 1304. https://doi.org/10.3390/biomedicines9101304

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

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