{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T23:43:27Z","timestamp":1773445407929,"version":"3.50.1"},"reference-count":31,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,4,11]],"date-time":"2022-04-11T00:00:00Z","timestamp":1649635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FEDER funds through the Operational Programme Competitiveness Factors, COMPETE and national funds by Foundation for Science and Technology (FCT)  and EU project FSE-FESR","award":["POCI-01-0145-FEDER-029164, PT-OPENSCREEN-NORTE-01-0145-FEDE, PON-RI 2014-2020R-085468, UIDP\/00081\/2020,"],"award-info":[{"award-number":["POCI-01-0145-FEDER-029164, PT-OPENSCREEN-NORTE-01-0145-FEDE, PON-RI 2014-2020R-085468, UIDP\/00081\/2020,"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Human monoamine oxidases (hMAOs) are well-established targets for the treatment of neurological disorders such as depression, Parkinson\u2019s disease and Alzheimer\u2019s disease. Despite the efforts carried out over the years, few selective and reversible MAO inhibitors are on the market. Thus, a continuous search for new compounds is needed. Herein, MAO inhibitors were searched among the non-chiral constituents of Bergamot Essential Oil (BEO) with the aid of computational tools. Accordingly, molecular modeling simulations were carried out on both hMAO-A and hMAO-B for the selected constituents. The theoretically predicted target recognition was then used to select the most promising compounds. Among the screened compounds, Bergamottin, a furocoumarin, showed selective hMAO-B inhibitory activity, fitting its active site well. Molecular dynamics simulations were used to deeply analyze the target recognition and to rationalize the selectivity preference. In agreement with the computational results, experimental studies confirmed both the hMAO inhibition properties of Bergamottin and its preference for the isoform B.<\/jats:p>","DOI":"10.3390\/molecules27082467","type":"journal-article","created":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T02:48:59Z","timestamp":1649731739000},"page":"2467","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Molecular Modeling and Experimental Evaluation of Non-Chiral Components of Bergamot Essential Oil with Inhibitory Activity against Human Monoamine Oxidases"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3936-3573","authenticated-orcid":false,"given":"Raffaella","family":"Catalano","sequence":"first","affiliation":[{"name":"Department of Health Sciences, University \u201cMagna Graecia\u201d of Catanzaro, Campus Universitario \u201cS. Venuta\u201d, Viale Europa, Loc. Germaneto, 88100 Catanzaro, Italy"},{"name":"Net4Science s.r.l., University \u201cMagna Graecia\u201d of Catanzaro, Campus Universitario \u201cS. Venuta\u201d, Viale Europa, Loc. Germaneto, 88100 Catanzaro, Italy"}]},{"given":"Francesca","family":"Procopio","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University \u201cMagna Graecia\u201d of Catanzaro, Campus Universitario \u201cS. Venuta\u201d, Viale Europa, Loc. Germaneto, 88100 Catanzaro, Italy"}]},{"given":"Daniel","family":"Chavarria","sequence":"additional","affiliation":[{"name":"CIQUP\/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal"}]},{"given":"Sofia","family":"Benfeito","sequence":"additional","affiliation":[{"name":"CIQUP\/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal"}]},{"given":"Stefano","family":"Alcaro","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University \u201cMagna Graecia\u201d of Catanzaro, Campus Universitario \u201cS. Venuta\u201d, Viale Europa, Loc. Germaneto, 88100 Catanzaro, Italy"},{"name":"Net4Science s.r.l., University \u201cMagna Graecia\u201d of Catanzaro, Campus Universitario \u201cS. Venuta\u201d, Viale Europa, Loc. Germaneto, 88100 Catanzaro, Italy"},{"name":"CRISEA\u2014Centro di Ricerca e Servizi Avanzati per l\u2019Innovazione Rurale, 88055 Belcastro, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1050-2402","authenticated-orcid":false,"given":"Fernanda","family":"Borges","sequence":"additional","affiliation":[{"name":"CIQUP\/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6235-8161","authenticated-orcid":false,"given":"Francesco","family":"Ortuso","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University \u201cMagna Graecia\u201d of Catanzaro, Campus Universitario \u201cS. Venuta\u201d, Viale Europa, Loc. Germaneto, 88100 Catanzaro, Italy"},{"name":"Net4Science s.r.l., University \u201cMagna Graecia\u201d of Catanzaro, Campus Universitario \u201cS. Venuta\u201d, Viale Europa, Loc. Germaneto, 88100 Catanzaro, Italy"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/nrn1883","article-title":"The therapeutic potential of monoamine oxidase inhibitors","volume":"7","author":"Youdim","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_2","first-page":"79","article-title":"Enzymology of monoamine oxidase","volume":"4","author":"Tipton","year":"1986","journal-title":"Cell Biochem. Funct. Cell. Biochem. Its Modul. By Act. Agents Or Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1146\/annurev.neuro.22.1.197","article-title":"Monoamine oxidase: From genes to behavior","volume":"22","author":"Shih","year":"1999","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S287","DOI":"10.1038\/sj.bjp.0706464","article-title":"Monoamine oxidase: Isoforms and inhibitors in Parkinson\u2019s disease and depressive illness","volume":"147","author":"Youdim","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9750","DOI":"10.1073\/pnas.1633804100","article-title":"Insights into the mode of inhibition of human mitochondrial monoamine oxidase B from high-resolution crystal structures","volume":"100","author":"Binda","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5848","DOI":"10.1021\/jm070677y","article-title":"Structures of human monoamine oxidase B complexes with selective noncovalent inhibitors: Safinamide and coumarin analogs","volume":"50","author":"Binda","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/S0014-5793(04)00209-1","article-title":"Crystal structure of human monoamine oxidase B, a drug target enzyme monotopically inserted into the mitochondrial outer membrane","volume":"564","author":"Binda","year":"2004","journal-title":"FEBS Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5739","DOI":"10.1073\/pnas.0710626105","article-title":"Structure of human monoamine oxidase A at 2.2-\u00c5 resolution: The control of opening the entry for substrates\/inhibitors","volume":"105","author":"Son","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"340","DOI":"10.3389\/fphar.2016.00340","article-title":"Inhibitors of MAO-A and MAO-B in psychiatry and neurology","volume":"7","author":"Finberg","year":"2016","journal-title":"Front. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1080\/13543776.2018.1427735","article-title":"MAO inhibitors and their wider applications: A patent review","volume":"28","author":"Carradori","year":"2018","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"111903","DOI":"10.1016\/j.ejmech.2019.111903","article-title":"Mediterranean products as promising source of multi-target agents in the treatment of metabolic syndrome","volume":"186","author":"Bagetta","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"420","DOI":"10.3389\/fphar.2017.00420","article-title":"Anticancer potential of citrus juices and their extracts: A systematic review of both preclinical and clinical studies","volume":"8","author":"Cirmi","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.colsurfb.2013.09.017","article-title":"Anticancer activity of liposomal bergamot essential oil (BEO) on human neuroblastoma cells","volume":"112","author":"Celia","year":"2013","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/ptr.5734","article-title":"Clinical pharmacology of Citrus bergamia: A systematic review","volume":"31","author":"Mannucci","year":"2017","journal-title":"Phytother. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"152","DOI":"10.3390\/encyclopedia1010016","article-title":"Bergamot oil: Botany, production, pharmacology","volume":"1","author":"Valussi","year":"2021","journal-title":"Encyclopedia"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Baron, G., Altomare, A., Mol, M., Garcia, J.L., Correa, C., Raucci, A., Mancinelli, L., Mazzotta, S., Fumagalli, L., and Trunfio, G. (2021). Analytical profile and antioxidant and anti-inflammatory activities of the enriched polyphenol fractions isolated from bergamot fruit and leave. Antioxidants, 10.","DOI":"10.3390\/antiox10020141"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"D1388","DOI":"10.1093\/nar\/gkaa971","article-title":"PubChem in 2021: New data content and improved web interfaces","volume":"49","author":"Kim","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_18","unstructured":"(2021). Schr\u00f6dinger Release 2021-4: LigPrep, Schr\u00f6dinger, LLC."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4203","DOI":"10.1021\/acs.jmedchem.8b00357","article-title":"Tight-binding inhibition of human monoamine oxidase B by chromone analogs: A kinetic, crystallographic, and biological analysis","volume":"61","author":"Reis","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_21","unstructured":"(2021). Schr\u00f6dinger Release 2021-4: Protein Preparation Wizard, Schr\u00f6dinger, LLC."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1002\/jcc.20292","article-title":"Integrated modeling program, applied chemical theory (IMPACT)","volume":"26","author":"Banks","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_23","unstructured":"(2021). Schr\u00f6dinger Release 2021-4: Glide, Schr\u00f6dinger, LLC."},{"key":"ref_24","unstructured":"(2021). Schr\u00f6dinger Release 2021-4: Desmond Molecular Dynamics System, Maestro-Desmond Interoperability Tools, Schr\u00f6dinger. D. E. Shaw Research."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Bowers, K.J., Chow, D.E., Xu, H., Dror, R.O., Eastwood, M.P., Gregersen, B.A., Klepeis, J.L., Kolossvary, I., Moraes, M.A., and Sacerdoti, F.D. (2006, January 11\u201317). Scalable algorithms for molecular dynamics simulations on commodity clusters. Proceedings of the SC\u201906: 2006 ACM\/IEEE Conference on Supercomputing, Tampa, FL, USA.","DOI":"10.1145\/1188455.1188544"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Berendsen, H.J., Postma, J.P., van Gunsteren, W.F., and Hermans, J. (1981). Interaction models for water in relation to protein hydration. Intermolecular Forces, Springer.","DOI":"10.1007\/978-94-015-7658-1_21"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1007\/s00214-009-0590-4","article-title":"Effects of bundling on the properties of the SPC water model","volume":"125","author":"Fuhrmans","year":"2010","journal-title":"Theor. Chem. Acc."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/0021-9991(77)90098-5","article-title":"Numerical integration of the cartesian equations of motion of a system with constraints: Molecular dynamics of n-alkanes","volume":"23","author":"Ryckaert","year":"1977","journal-title":"J. Comput. Phys."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1002\/jcc.540161003","article-title":"Algorithms for constrained molecular dynamics","volume":"16","author":"Barth","year":"1995","journal-title":"J. Comput. chemistry"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.molstruc.2019.01.060","article-title":"Development of piperic acid-based monoamine oxidase inhibitors: Synthesis, structural characterization and biological evaluation","volume":"1182","author":"Chavarria","year":"2019","journal-title":"J. Mol. Struct."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"40541","DOI":"10.1038\/srep40541","article-title":"Ciproxifan, a H3 receptor inverse agonist, reversibly inhibits human monoamine oxidase A and B","volume":"7","author":"Hagenow","year":"2017","journal-title":"Sci. Rep."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/8\/2467\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:52:07Z","timestamp":1760136727000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/8\/2467"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,11]]},"references-count":31,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["molecules27082467"],"URL":"https:\/\/doi.org\/10.3390\/molecules27082467","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,11]]}}}