{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T12:01:34Z","timestamp":1786449694074,"version":"build-2736575974"},"reference-count":179,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T00:00:00Z","timestamp":1667174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A computational protocol aimed to design new antioxidants with versatile behavior is presented. It is called Computer-Assisted Design of Multifunctional Antioxidants and is based on chemical properties (CADMA-Chem). The desired multi-functionality consists of in different methods of antioxidant protection combined with neuroprotection, although the protocol can also be used to pursue other health benefits. The dM38 melatonin derivative is used as a study case to illustrate the protocol in detail. This was found to be a highly promising candidate for the treatment of neurodegeneration, in particular Parkinson\u2019s and Alzheimer\u2019s diseases. This also has the desired properties of an oral-drug, which is significantly better than Trolox for scavenging free radicals, and has chelates redox metals, prevents the \u25cfOH production, via Fenton-like reactions, repairs oxidative damage in biomolecules (lipids, proteins, and DNA), and acts as a polygenic neuroprotector by inhibiting catechol-O-methyl transferase (COMT), acetylcholinesterase (AChE) and monoamine oxidase B (MAOB). To the best of our best knowledge, CADMA-Chem is currently the only protocol that simultaneously involves the analyses of drug-like behavior, toxicity, manufacturability, versatile antioxidant protection, and receptor\u2013ligand binding affinities. It is expected to provide a starting point that helps to accelerate the discovery of oral drugs with the potential to prevent, or slow down, multifactorial human health disorders.<\/jats:p>","DOI":"10.3390\/ijms232113246","type":"journal-article","created":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T06:42:17Z","timestamp":1667371337000},"page":"13246","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["CADMA-Chem: A Computational Protocol Based on Chemical Properties Aimed to Design Multifunctional Antioxidants"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1443-4136","authenticated-orcid":false,"given":"Eduardo","family":"Guzman-Lopez","sequence":"first","affiliation":[{"name":"Departamento de Qu\u00edmica, Universidad Aut\u00f3noma Metropolitana-Iztapalapa, Av. Ferrocarril San Rafael Atlixco 186, Col. Leyes de Reforma 1A Secci\u00f3n, Mexico City 09310, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4959-4105","authenticated-orcid":false,"given":"Miguel","family":"Reina","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Inorg\u00e1nica y Nuclear, Facultad de Qu\u00edmica, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Perez-Gonzalez","sequence":"additional","affiliation":[{"name":"CONACYT-Universidad Aut\u00f3noma Metropolitana-Iztapalapa, Av. Ferrocarril San Rafael Atlixco 186, Col. Leyes de Reforma 1A Secci\u00f3n, Mexico City 09310, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3591-0613","authenticated-orcid":false,"given":"Misaela","family":"Francisco-Marquez","sequence":"additional","affiliation":[{"name":"Instituto Polit\u00e9cnico Nacional-UPIICSA, T\u00e9 950, Col. Granjas M\u00e9xico, Mexico City 08400, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3387-763X","authenticated-orcid":false,"given":"Luis","family":"Hernandez-Ayala","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica, Universidad Aut\u00f3noma Metropolitana-Iztapalapa, Av. Ferrocarril San Rafael Atlixco 186, Col. Leyes de Reforma 1A Secci\u00f3n, Mexico City 09310, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romina","family":"Casta\u00f1eda-Arriaga","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica, Universidad Aut\u00f3noma Metropolitana-Iztapalapa, Av. Ferrocarril San Rafael Atlixco 186, Col. Leyes de Reforma 1A Secci\u00f3n, Mexico City 09310, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1470-3060","authenticated-orcid":false,"given":"Annia","family":"Galano","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica, Universidad Aut\u00f3noma Metropolitana-Iztapalapa, Av. Ferrocarril San Rafael Atlixco 186, Col. Leyes de Reforma 1A Secci\u00f3n, Mexico City 09310, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1093\/geront\/gnv130","article-title":"Lifespan and healthspan: Past, present, and promise","volume":"55","author":"Crimmins","year":"2015","journal-title":"Gerontologist"},{"key":"ref_2","unstructured":"United Nations (2019). World Population Prospects 2019: Highlights, United Nations."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e2019536118","DOI":"10.1073\/pnas.2019536118","article-title":"Demographic perspectives on the rise of longevity","volume":"118","author":"Vaupel","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/s41536-021-00169-5","article-title":"Longevity leap: Mind the healthspan gap","volume":"6","author":"Garmany","year":"2021","journal-title":"NPJ Regen. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.tem.2019.06.001","article-title":"Interactive and Multifactorial Mechanisms of Calcific Vascular and Valvular Disease","volume":"30","author":"Demer","year":"2019","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"BSR20200265","DOI":"10.1042\/BSR20200265","article-title":"Colorectal cancer (CRC) as a multifactorial disease and its causal correlations with multiple signaling pathways","volume":"40","author":"Wan","year":"2020","journal-title":"Biosci. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.1177\/13591053211037737","article-title":"Multifactorial causal beliefs and colorectal cancer screening: A structural equation modeling investigation","volume":"27","author":"Allen","year":"2021","journal-title":"J. Health Psychol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.currproblcancer.2018.01.014","article-title":"Risk factors for prostate cancer: A multifactorial case-control study","volume":"42","author":"Malik","year":"2018","journal-title":"Curr. Probl. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/j.eururo.2018.02.023","article-title":"Complex Polygenic Nature of Testicular Germ Cell Cancer Suggests Multifactorial Aetiology","volume":"73","author":"Skotheim","year":"2018","journal-title":"Eur. Urol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1007\/978-1-61779-612-8_26","article-title":"Multifactorial etiology of gastric cancer","volume":"863","author":"Zabaleta","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s13353-021-00679-4","article-title":"Genome-wide analysis of genetic predisposition to common polygenic cancers","volume":"63","author":"Nazarian","year":"2022","journal-title":"J. Appl. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Guerra, J.V.S., Dias, M.M.G., Brilhante, A.J.V.C., Terra, M.F., Garc\u00eda-Ar\u00e9valo, M., and Figueira, A.C.M. (2021). Multifactorial basis and therapeutic strategies in metabolism-related diseases. Nutrients, 13.","DOI":"10.3390\/nu13082830"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"107496","DOI":"10.1016\/j.pharmthera.2020.107496","article-title":"Berberine in the treatment of metabolism-related chronic diseases: A drug cloud (dCloud) effect to target multifactorial disorders","volume":"209","author":"Kong","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"105014","DOI":"10.1016\/j.nbd.2020.105014","article-title":"Ceramide signalling in inherited and multifactorial brain metabolic diseases","volume":"143","author":"Pant","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.copbio.2019.12.006","article-title":"Organs-on-a-chip as model systems for multifactorial musculoskeletal diseases","volume":"63","author":"Arrigoni","year":"2020","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.livres.2022.05.002","article-title":"Non-alcoholic fatty liver disease development: A multifactorial pathogenic phenomena","volume":"6","author":"Bashir","year":"2022","journal-title":"Liver Res."},{"key":"ref_17","unstructured":"Brocardo, P.S., and Gil-Mohapel, J. (2012). Mechanisms underlying the neuropathology of huntington\u2019s disease, a multifactorial neurodegenerative disorder. Neuropathology: New Research, Nova Science Publishers Inc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1016\/j.bbadis.2012.02.005","article-title":"Oxidative stress underlying axonal degeneration in adrenoleukodystrophy: A paradigm for multifactorial neurodegenerative diseases?","volume":"1822","author":"Galea","year":"2012","journal-title":"Biochim. Biophys. Acta, Mol. Basis Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2787","DOI":"10.1007\/s12035-015-9145-y","article-title":"Role of MicroRNA Let-7 in Modulating Multifactorial Aspect of Neurodegenerative Diseases: An Overview","volume":"53","author":"Shamsuzzama","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1038\/s41433-019-0646-1","article-title":"Early retinal neurodegeneration in preclinical diabetic retinopathy: A multifactorial investigation","volume":"34","author":"Toprak","year":"2020","journal-title":"Eye"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1007\/s12223-022-00977-2","article-title":"Exploring the multifactorial aspects of Gut Microbiome in Parkinson\u2019s Disease","volume":"67","author":"Pavan","year":"2022","journal-title":"Folia Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.sleep.2017.03.026","article-title":"Multifactorial sleep disturbance in Parkinson\u2019s disease","volume":"35","author":"Albers","year":"2017","journal-title":"Sleep Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s10072-018-3585-x","article-title":"Understanding multifactorial architecture of Parkinson\u2019s disease: Pathophysiology to management","volume":"40","author":"Kaur","year":"2019","journal-title":"Neurol. Sci."},{"key":"ref_24","first-page":"502","article-title":"Parkinson\u2019s disease as multifactorial oxidative neurodegeneration: Implications for integrative management","volume":"5","author":"Kidd","year":"2000","journal-title":"Altern. Med. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Riess, O., and Kr\u00fcger, R. (1999). Parkinson\u2019s disease\u2014A multifactorial neurodegenerative disorder. Diagnosis and Treatment of Parkinson\u2019s Disease\u2014State of the Art, Springer.","DOI":"10.1007\/978-3-7091-6360-3_6"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/s12035-020-02116-9","article-title":"Multi-Target Drug Candidates for Multifactorial Alzheimer\u2019s Disease: AChE and NMDAR as Molecular Targets","volume":"58","author":"Uddin","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2380","DOI":"10.2174\/1568026620666200601161703","article-title":"Emerging proof of protein misfolding and interactions in multifactorial alzheimer\u2019s disease","volume":"20","author":"Uddin","year":"2020","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Dhakal, S., Kushairi, N., Phan, C.W., Adhikari, B., Sabaratnam, V., and Macreadie, I. (2019). Dietary polyphenols: A multifactorial strategy to target alzheimer\u2019s disease. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20205090"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"S107","DOI":"10.3233\/JAD-179921","article-title":"Multifactorial Hypothesis and Multi-Targets for Alzheimer\u2019s Disease","volume":"64","author":"Gong","year":"2018","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1097\/WCO.0000000000000497","article-title":"The vascular facet of late-onset Alzheimer\u2019s disease: An essential factor in a complex multifactorial disorder","volume":"30","author":"Hachinski","year":"2017","journal-title":"Curr. Opin. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Behl, T., Makkar, R., Sehgal, A., Singh, S., Sharma, N., Zengin, G., Bungau, S., Andronie-Cioara, F.L., Munteanu, M.A., and Brisc, M.C. (2021). Current trends in neurodegeneration: Cross talks between oxidative stress, cell death, and inflammation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22147432"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e551","DOI":"10.1016\/S2468-2667(20)30190-0","article-title":"The burden of neurological diseases in Europe: An analysis for the Global Burden of Disease Study 2017","volume":"5","author":"Deuschl","year":"2020","journal-title":"Lancet Public Health"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s13195-020-00601-w","article-title":"Relevance of biomarkers across different neurodegenerative","volume":"12","author":"Ehrenberg","year":"2020","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_34","unstructured":"Alzheimer\u2019s Association (2022). 2022 Alzheimer\u2019s Disease Facts and Figures, Alzheimer\u2019s Association."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Abramov, A.Y., Potapova, E.V., Dremin, V.V., and Dunaev, A.V. (2020). Interaction of oxidative stress and misfolded proteins in the mechanism of neurodegeneration. Life, 10.","DOI":"10.3390\/life10070101"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ashok, A., Andrabi, S.S., Mansoor, S., Kuang, Y., Kwon, B.K., and Labhasetwar, V. (2022). Antioxidant Therapy in Oxidative Stress-Induced Neurodegenerative Diseases: Role of Nanoparticle-Based Drug Delivery Systems in Clinical Translation. Antioxidants, 11.","DOI":"10.3390\/antiox11020408"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Buccellato, F.R., D\u2019Anca, M., Galimberti, D., Fenoglio, C., and Scarpini, E. (2021). Role of oxidative damage in alzheimer\u2019s disease and neurodegeneration: From pathogenic mechanisms to biomarker discovery. Antioxidants, 10.","DOI":"10.3390\/antiox10091353"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Espin\u00f3s, C., Galindo, M.I., Garc\u00eda-Gimeno, M.A., Ib\u00e1\u00f1ez-Cabellos, J.S., Mart\u00ednez-Rubio, D., Mill\u00e1n, J.M., Rodrigo, R., Sanz, P., Seco-Cervera, M., and Sevilla, T. (2020). Oxidative stress, a crossroad between rare diseases and neurodegeneration. Antioxidants, 9.","DOI":"10.3390\/antiox9040313"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Gkekas, I., Gioran, A., Boziki, M.K., Grigoriadis, N., Chondrogianni, N., and Petrakis, S. (2021). Oxidative stress and neurodegeneration: Interconnected processes in polyq diseases. Antioxidants, 10.","DOI":"10.3390\/antiox10091450"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Jantas, D., and Laso\u0144, W. (2021). Preclinical evidence for the interplay between oxidative stress and rip1-dependent cell death in neurodegeneration: State of the art and possible therapeutic implications. Antioxidants, 10.","DOI":"10.3390\/antiox10101518"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Jurcau, A. (2021). Insights into the pathogenesis of neurodegenerative diseases: Focus on mitochondrial dysfunction and oxidative stress. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111847"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/s41419-020-03355-3","article-title":"The redox language in neurodegenerative diseases: Oxidative post-translational modifications by hydrogen peroxide","volume":"12","author":"Lee","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Limanaqi, F., Biagioni, F., Mastroiacovo, F., Polzella, M., Lazzeri, G., and Fornai, F. (2020). Merging the multi-target effects of phytochemicals in neurodegeneration: From oxidative stress to protein aggregation and inflammation. Antioxidants, 9.","DOI":"10.3390\/antiox9101022"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"S109","DOI":"10.3233\/JAD-201074","article-title":"Hypoxia, Oxidative Stress, and Inflammation: Three Faces of Neurodegenerative Diseases","volume":"82","author":"Merelli","year":"2021","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Michalska, P., and Le\u00f3n, R. (2020). When it comes to an end: Oxidative stress crosstalk with protein aggregation and neuroinflammation induce neurodegeneration. Antioxidants, 9.","DOI":"10.3390\/antiox9080740"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6512","DOI":"10.1002\/anie.201811122","article-title":"Dopamine, Oxidative Stress and Protein\u2013Quinone Modifications in Parkinson\u2019s and Other Neurodegenerative Diseases","volume":"58","author":"Monzani","year":"2019","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Mor, A., Tankiewicz-Kwedlo, A., Krupa, A., and Pawlak, D. (2021). Role of kynurenine pathway in oxidative stress during neurodegenerative disorders. Cells, 10.","DOI":"10.3390\/cells10071603"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.freeradbiomed.2021.07.002","article-title":"Protein S-nitrosylation and oxidation contribute to protein misfolding in neurodegeneration","volume":"172","author":"Nakamura","year":"2021","journal-title":"Free Rad. Biol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Picca, A., Calvani, R., Coelho-J\u00fanior, H.J., Landi, F., Bernabei, R., and Marzetti, E. (2020). Mitochondrial dysfunction, oxidative stress, and neuroinflammation: Intertwined roads to neurodegeneration. Antioxidants, 9.","DOI":"10.3390\/antiox9080647"},{"key":"ref_50","first-page":"77","article-title":"A Review on Antioxidants as Therapeutic in Use of Oxidative Stress and Neurodegenerative Disease","volume":"13","author":"Rana","year":"2022","journal-title":"Int. J. Pharm. Qual. Assur."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.2174\/0929867328666211101100632","article-title":"Effects of Polyphenols in Aging and Neurodegeneration Associated with Oxidative Stress","volume":"29","author":"Rivas","year":"2022","journal-title":"Curr. Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.jare.2021.09.005","article-title":"Interplay of gut microbiota and oxidative stress: Perspective on neurodegeneration and neuroprotection","volume":"38","author":"Shandilya","year":"2022","journal-title":"J. Adv. Res."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Shi, X., Li, P., Liu, H., and Prokosch, V. (2022). Oxidative Stress, Vascular Endothelium, and the Pathology of Neurodegeneration in Retina. Antioxidants, 11.","DOI":"10.3390\/antiox11030543"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Simpson, D.S.A., and Oliver, P.L. (2020). Ros generation in microglia: Understanding oxidative stress and inflammation in neurodegenerative disease. Antioxidants, 9.","DOI":"10.3390\/antiox9080743"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3133","DOI":"10.1007\/s11033-020-05354-1","article-title":"Neurodegeneration by oxidative stress: A review on prospective use of small molecules for neuroprotection","volume":"47","author":"Singh","year":"2020","journal-title":"Mol. Biol. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Teleanu, D.M., Niculescu, A.G., Lungu, I.I., Radu, C.I., Vlad\u00e2cenco, O., Roza, E., Cost\u0103chescu, B., Grumezescu, A.M., and Teleanu, R.I. (2022). An Overview of Oxidative Stress, Neuroinflammation and Neurodegenerative Diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23115938"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"173412","DOI":"10.1016\/j.ejphar.2020.173412","article-title":"Neuroprotective role of polyphenols against oxidative stress-mediated neurodegeneration","volume":"886","author":"Uddin","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1111\/j.1471-4159.2006.03907.x","article-title":"Oxidative stress and neurodegeneration: Where are we now?","volume":"97","author":"Halliwell","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1152\/physrev.00018.2001","article-title":"Free radicals in the physiological control of cell function","volume":"82","year":"2002","journal-title":"Physiol. Rev."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1196\/annals.1427.010","article-title":"Evidence of oxidative stress in Alzheimer\u2019s disease brain and antioxidant therapy: Lights and shadows","volume":"1147","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S1474-4422(07)70327-7","article-title":"Mitochondria in the aetiology and pathogenesis of Parkinson\u2019s disease","volume":"7","author":"Schapira","year":"2008","journal-title":"Lancet Neurol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.neuro.2008.01.007","article-title":"Oxidative insults induce DJ-1 upregulation and redistribution: Implications for neuroprotection","volume":"29","author":"Lev","year":"2008","journal-title":"Neurotoxicology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.molcel.2009.02.013","article-title":"PINK1-Associated Parkinson\u2019s Disease Is Caused by Neuronal Vulnerability to Calcium-Induced Cell Death","volume":"33","author":"Gandhi","year":"2009","journal-title":"Mol. Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1021\/jm7009364","article-title":"Multi-target-directed ligands to combat neurodegenerative diseases","volume":"51","author":"Cavalli","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Chopade, P., Chopade, N., Zhao, Z.M., Mitragotri, S., Liao, R., and Suja, V.C. (2022). Alzheimer\u2019s and Parkinson\u2019s disease therapies in the clinic. Bioeng. Transl. Med., e10367.","DOI":"10.1002\/btm2.10367"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"108352","DOI":"10.1016\/j.neuropharm.2020.108352","article-title":"Efficacy of acetylcholinesterase inhibitors in Alzheimer\u2019s disease","volume":"190","author":"Marucci","year":"2021","journal-title":"Neuropharmacology"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Moreta, M.P.G., Burgos-Alonso, N., Torrecilla, M., Marco-Contelles, J., and Bruzos-Cid\u00f3n, C. (2021). Efficacy of acetylcholinesterase inhibitors on cognitive function in alzheimer\u2019s disease. Review of reviews. Biomedicines, 9.","DOI":"10.3390\/biomedicines9111689"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/s40265-014-0343-0","article-title":"Catechol-O-methyltransferase inhibitors in Parkinson\u2019s disease","volume":"75","year":"2015","journal-title":"Drugs"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4813","DOI":"10.1007\/s10072-021-05481-y","article-title":"Remarkable clinical responses of non-fluctuating Parkinson\u2019s disease (PD) after alternating catechol O-methyltransferase inhibitors: Case series switching from entacapone 200~300 mg\/day to opicapone 25 mg\/day","volume":"42","author":"Nakamagoe","year":"2021","journal-title":"Neurol. Sci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s40263-021-00888-9","article-title":"COMT Inhibitors in the Management of Parkinson\u2019s Disease","volume":"36","author":"Fabbri","year":"2022","journal-title":"CNS Drugs"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1177\/1060028020974560","article-title":"Opicapone (Ongentys): A New COMT Inhibitor for the Treatment of Parkinson\u2019s Disease","volume":"55","author":"Onge","year":"2021","journal-title":"Ann. Pharmacother."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1007\/s00702-018-1952-7","article-title":"Inhibitors of MAO-B and COMT: Their effects on brain dopamine levels and uses in Parkinson\u2019s disease","volume":"126","author":"Finberg","year":"2019","journal-title":"J. Neural Transm."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1007\/s00702-022-02465-w","article-title":"A critical appraisal of MAO-B inhibitors in the treatment of Parkinson\u2019s disease","volume":"129","author":"Jost","year":"2022","journal-title":"J. Neural Transm."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"6045","DOI":"10.2174\/0929867328666210203204710","article-title":"Monoamine oxidase-B (MAO-B) inhibitors in the treatment of alzheimer\u2019s and parkinson\u2019s disease","volume":"28","year":"2021","journal-title":"Curr. Med. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"847","DOI":"10.2174\/1386207323666200402090557","article-title":"Treatment of parkinson\u2019s disease by MAO-B inhibitors, new therapies and future challenges\u2014A mini-review","volume":"23","author":"Parambi","year":"2020","journal-title":"Comb. Chem. High Throughput Screen."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.2174\/1568026620666200416085330","article-title":"Role of flavonoids in neurodegenerative diseases: Limitations and future perspectives","volume":"20","author":"Maan","year":"2020","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1021\/acs.chemrev.8b00138","article-title":"Development of multifunctional molecules as potential therapeutic candidates for Alzheimer\u2019s disease, Parkinson\u2019s disease, and amyotrophic lateral sclerosis in the last decade","volume":"119","author":"Savelieff","year":"2019","journal-title":"Chem. Rev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1080\/17460441.2022.2072827","article-title":"What are the challenges with multi-targeted drug design for complex diseases?","volume":"17","author":"Matosiuk","year":"2022","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"366","DOI":"10.2174\/1568026622666220201151248","article-title":"The Design of Multi-target Drugs to Treat Cardiovascular Diseases: Two (or more) Birds on One Stone","volume":"22","author":"Caruso","year":"2022","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Catto, M., Trisciuzzi, D., Alberga, D., Mangiatordi, G.F., and Nicolotti, O. (2019). Multitarget drug design for neurodegenerative diseases. Methods in Pharmacology and Toxicology, Springer Nature.","DOI":"10.1007\/7653_2018_17"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3491","DOI":"10.2174\/0929867325666180111101843","article-title":"Multi-target directed drugs as a modern approach for drug design towards Alzheimer\u2019s disease: An update","volume":"25","author":"Dias","year":"2018","journal-title":"Curr. Med. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.ejmech.2017.02.043","article-title":"Design, synthesis and evaluation of novel feruloyl-donepezil hybrids as potential multitarget drugs for the treatment of Alzheimer\u2019s disease","volume":"130","author":"Dias","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"239","DOI":"10.2174\/1570159X1203140511153200","article-title":"Multi-Target directed drugs: A modern approach for design of new drugs for the treatment of Alzheimer\u2019s disease","volume":"12","author":"Dias","year":"2014","journal-title":"Curr. Neuropharmacol."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Fu, Y., Mu, Y., Lei, H., Wang, P., Li, X., Leng, Q., Han, L., Qu, X., Wang, Z., and Huang, X. (2016). Design, synthesis and evaluation of novel tacrine-ferulic acid hybrids as multifunctional drug candidates against Alzheimer\u2019s disease. Molecules, 21.","DOI":"10.3390\/molecules21101338"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"348","DOI":"10.2174\/1385272823666191021124443","article-title":"Molecular hybridization as a tool in the design of multi-target directed drug candidates for neurodegenerative diseases","volume":"18","author":"Gontijo","year":"2020","journal-title":"Curr. Neuropharmacol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Halder, A.K., Moura, A.S., and Cordeiro, M.N.D.S. (2019). Advanced chemometric modeling approaches for the design of multitarget drugs against neurodegenerative diseases. Methods in Pharmacology and Toxicology, Springer Nature.","DOI":"10.1007\/7653_2018_14"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.2174\/1568026619666190619115735","article-title":"Molecular hybridization as a tool for designing multitarget drug candidates for complex diseases","volume":"19","author":"Ivasiv","year":"2019","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Katsamakas, S., and Hadjipavlou-Litina, D. (2019). Computational design of multitarget drugs against Alzheimer\u2019s disease. Methods in Pharmacology and Toxicology, Springer Nature.","DOI":"10.1007\/7653_2018_25"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.2174\/0929867321666140303144625","article-title":"Multi-target drug design approaches for multifactorial diseases: From neurodegenerative to cardiovascular applications","volume":"21","author":"Katselou","year":"2014","journal-title":"Curr. Med. Chem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"726","DOI":"10.2174\/1570159X16666180315141643","article-title":"Changing paradigm from one target one ligand towards multi-target directed ligand design for key drug targets of alzheimer disease: An important role of in silico methods in multi-target directed ligands design","volume":"16","author":"Kumar","year":"2018","journal-title":"Curr. Neuropharmacol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/j.bmc.2016.11.048","article-title":"Multitarget drug design strategy against Alzheimer\u2019s disease: Homoisoflavonoid Mannich base derivatives serve as acetylcholinesterase and monoamine oxidase B dual inhibitors with multifunctional properties","volume":"25","author":"Li","year":"2017","journal-title":"Bioorg. Med. Chem."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Ortiz, C.J.C., de Freitas Silva, M., Gontijo, V.S., Viegas, F.P.D., Dias, K.S.T., and Viegas, C. (2019). Design of multi-target directed ligands as a modern approach for the development of innovative drug candidates for Alzheimer\u2019s disease. Methods in Pharmacology and Toxicology, Springer Nature.","DOI":"10.1007\/7653_2018_2"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"953","DOI":"10.4155\/fmc-2017-0039","article-title":"Multitarget drug design strategy in Alzheimer\u2019s disease: Focus on cholinergic transmission and amyloid-\u03b2 aggregation","volume":"9","author":"Simoni","year":"2017","journal-title":"Future Med. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.2174\/1389557521666210212151127","article-title":"Multi-target drug design of anti-alzheimer\u2019s disease based on tacrine","volume":"21","author":"Tian","year":"2021","journal-title":"Mini-Rev. Med. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.ejmech.2014.01.060","article-title":"Multifunctional compounds: Smart molecules for multifactorial diseases","volume":"76","author":"Bansal","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/nrd1799","article-title":"Computer-based de novo design of drug-like molecules","volume":"4","author":"Schneider","year":"2005","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"46","author":"Lipinski","year":"2001","journal-title":"Adv. Drug. Deliv. Rev."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1021\/cc9800071","article-title":"A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. 1. A Qualitative and Quantitative Characterization of Known Drug Databases","volume":"1","author":"Ghose","year":"1999","journal-title":"J. Comb. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2615","DOI":"10.1021\/jm020017n","article-title":"Molecular Properties That Influence the Oral Bioavailability of Drug Candidates","volume":"45","author":"Veber","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nrd3367","article-title":"Probing the links between in vitro potency, ADMET and physicochemical parameters","volume":"10","author":"Gleeson","year":"2011","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.2174\/15680266113139990034","article-title":"Understanding the molecular properties and metabolism of top prescribed drugs","volume":"13","author":"Zhong","year":"2013","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1021\/acs.jcim.6b00310","article-title":"Empirically Fitted Parameters for Calculating pKaValues with Small Deviations from Experiments Using a Simple Computational Strategy","volume":"56","author":"Galano","year":"2016","journal-title":"J. Chem. Inf. Model."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s00214-017-2179-7","article-title":"Estimation of empirically fitted parameters for calculating pK a values of thiols in a fast and reliable way","volume":"137","author":"Verastegui","year":"2018","journal-title":"Theor. Chem. Acc."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2430","DOI":"10.1002\/jcc.23409","article-title":"A computational methodology for accurate predictions of rate constants in solution: Application to the assessment of primary antioxidant activity","volume":"34","author":"Galano","year":"2013","journal-title":"J. Comput. Chem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0162-0134(97)00005-6","article-title":"Copper(II) interactions with nonsteroidal antiinflammatory agents. II. Anthranilic acid as a potential OH-inactivating ligand","volume":"68","author":"Miche","year":"1997","journal-title":"J. Inorg. Biochem."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1080\/10715760000300451","article-title":"Copper-ligand interactions and physiological free radical processes. Part 3. Influence of histidine, salicylic acid and anthranilic acid on copper-driven Fenton chemistry in vitro","volume":"32","author":"Gaubert","year":"2000","journal-title":"Free Radic. Res."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1007\/BF01998975","article-title":"Is copper pro- or anti-inflammatory? A reconciling view and a novel approach for the use of copper in the control of inflammation","volume":"39","author":"Berthon","year":"1993","journal-title":"Agents Actions"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1039\/d0mt00168f","article-title":"Neuron-glia: Understanding cellular copper homeostasis, its cross-talk and their contribution towards neurodegenerative diseases","volume":"12","author":"Bhattacharjee","year":"2020","journal-title":"Metallomics"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1021\/acs.molpharmaceut.7b00841","article-title":"The Pivotal Role of Copper in Neurodegeneration: A New Strategy for the Therapy of Neurodegenerative Disorders","volume":"15","author":"Giampietro","year":"2018","journal-title":"Mol. Pharm."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1016\/j.ccr.2012.03.013","article-title":"Copper, zinc and iron in neurodegenerative diseases (Alzheimer\u2019s, Parkinson\u2019s and prion diseases)","volume":"256","author":"Kozlowski","year":"2012","journal-title":"Coord. Chem. Rev."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"327","DOI":"10.3390\/toxics2020327","article-title":"Abnormal copper homeostasis: Mechanisms and roles in neurodegeneration","volume":"2","author":"Manto","year":"2014","journal-title":"Toxics"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.neuro.2019.07.007","article-title":"The role of zinc, copper, manganese and iron in neurodegenerative diseases","volume":"74","author":"Mezzaroba","year":"2019","journal-title":"Neurotoxicology"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1016\/j.ccr.2012.05.003","article-title":"Metal ions and amyloid fiber formation in neurodegenerative diseases. Copper, zinc and iron in Alzheimer\u2019s, Parkinson\u2019s and prion diseases","volume":"256","author":"Viles","year":"2012","journal-title":"Coord. Chem. Rev."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1021\/acs.chemrestox.7b00024","article-title":"Exploring Chemical Routes Relevant to the Toxicity of Paracetamol and Its meta-Analogue at a Molecular Level","volume":"30","author":"Galano","year":"2017","journal-title":"Chem. Res. Toxicol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"5687","DOI":"10.1046\/j.1432-1327.2000.01658.x","article-title":"Cytoprotective antioxidant function of tyrosine and tryptophan residues in transmembrane proteins","volume":"267","author":"Moosmann","year":"2000","journal-title":"Eur. J. Biochem."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"11323","DOI":"10.1021\/ja9027583","article-title":"Peculiar stability of amino acids and peptides from a radical perspective","volume":"131","author":"Watts","year":"2009","journal-title":"J. Am. Chem. Soc."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1063\/1.555805","article-title":"Critical Review of rate constants for reactions of hydrated electrons, hydrogen atoms and hydroxyl radicals (OH\/O\u2212 in Aqueous Solution","volume":"17","author":"Buxton","year":"1988","journal-title":"J. Phys. Chem. Ref. Data"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1016\/j.freeradbiomed.2009.01.001","article-title":"Efficient repair of protein radicals by ascorbate","volume":"46","author":"Domazou","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1007\/s00726-010-0610-7","article-title":"Reduction of protein radicals by GSH and ascorbate: Potential biological significance","volume":"39","author":"Gebicki","year":"2010","journal-title":"Amino Acids"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"16553","DOI":"10.1021\/ja205962b","article-title":"Hydrogen abstraction by chlorine atom from amino acids: Remarkable influence of polar effects on regioselectivity","volume":"133","author":"Oreilly","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1042\/BJ20151227","article-title":"Protein oxidation and peroxidation","volume":"473","author":"Davies","year":"2016","journal-title":"Biochem. J."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"3994","DOI":"10.1039\/B307031J","article-title":"H-atom abstraction by thiyl radicals from peptides and cyclic dipeptides. A theoretical study of reaction rates","volume":"5","author":"Reid","year":"2003","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"5342","DOI":"10.1021\/jp100375c","article-title":"Primary steps in the reaction of OH radicals with peptide systems: Perspective from a study of model amides","volume":"114","author":"Doan","year":"2010","journal-title":"J. Phys. Chem. A"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"9807","DOI":"10.1021\/jo3021538","article-title":"Reactivities of Amino Acid Derivatives Toward Hydrogen Abstraction by Cl\u2022 and OH\u2022","volume":"77","author":"Chan","year":"2012","journal-title":"J. Org. Chem."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1021\/jp2089559","article-title":"Conformation-dependent OH\/H2O2 hydrogen abstraction reaction cycles of Gly and Ala residues: A comparative theoretical study","volume":"116","author":"Owen","year":"2012","journal-title":"J. Phys. Chem. B"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"6862","DOI":"10.1002\/chem.201203862","article-title":"Computational study on the attack of \u00b7oH radicals on aromatic amino acids","volume":"19","author":"Mujika","year":"2013","journal-title":"Chem. Eur. J."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"8380","DOI":"10.1021\/jp501367w","article-title":"Hydrogen bonding constrains free radical reaction dynamics at serine and threonine residues in peptides","volume":"118","author":"Thomas","year":"2014","journal-title":"J. Phys. Chem. A"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.freeradbiomed.2014.01.014","article-title":"The kinetics of the reaction of nitrogen dioxide with iron(II)- and iron(III) cytochrome c","volume":"69","author":"Domazou","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"4970","DOI":"10.1039\/C4CP05688D","article-title":"Site reactivity in the free radicals induced damage to leucine residues: A theoretical study","volume":"17","author":"Medina","year":"2015","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1021\/jp505217q","article-title":"Hydrogen-atom abstraction from a model amino acid: Dependence on the attacking radical","volume":"119","author":"Amos","year":"2015","journal-title":"J. Phys. Chem. B"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"28525","DOI":"10.1039\/C5CP05090A","article-title":"A proton-electron sequential transfer mechanism: Theoretical evidence about its biological relevance","volume":"17","year":"2015","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"96714","DOI":"10.1039\/C5RA20618A","article-title":"Modelling the chemical repair of protein carbon-centered radicals formed via oxidative damage with dihydrolipoic acid","volume":"5","year":"2015","journal-title":"RSC Adv."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"5541","DOI":"10.1021\/jp951507c","article-title":"Nucleobase-Specific Quenching of Fluorescent Dyes. 1. Nucleobase One-Electron Redox Potentials and Their Correlation with Static and Dynamic Quenching Efficiencies","volume":"100","author":"Seidel","year":"1996","journal-title":"J. Phys. Chem."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"7063","DOI":"10.1021\/ja9609821","article-title":"Theoretical Studies of GG-Specific Photocleavage of DNA via Electron Transfer:\u2009 Significant Lowering of Ionization Potential and 5\u2018-Localization of HOMO of Stacked GG Bases in B-Form DNA","volume":"118","author":"Sugiyama","year":"1996","journal-title":"J. Am. Chem. Soc."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"10031","DOI":"10.1021\/ja961722m","article-title":"Induction of Strand Breaks in Single-Stranded Polyribonucleotides and DNA by Photoionization:\u2009 One Electron Oxidized Nucleobase Radicals as Precursors","volume":"118","author":"Melvin","year":"1996","journal-title":"J. Am. Chem. Soc."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S0009-2614(00)00391-2","article-title":"Electron affinities and ionization potentials of nucleotide bases","volume":"322","author":"Wetmore","year":"2000","journal-title":"Chem. Phys. Lett."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1021\/ar700245e","article-title":"Oxidatively Generated Damage to the Guanine Moiety of DNA: Mechanistic Aspects and Formation in Cells","volume":"41","author":"Cadet","year":"2008","journal-title":"Acc. Chem. Res."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1021\/ja962255b","article-title":"How easily oxidizable is DNA? One-electron reduction potentials of adenosine and guanosine radicals in aqueous solution","volume":"119","author":"Steenken","year":"1997","journal-title":"J. Am. Chem. Soc."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"12476","DOI":"10.1039\/c2cp40799j","article-title":"On the evolution of one-electron-oxidized deoxyguanosine in damaged DNA under physiological conditions: A DFT and ONIOM study on proton transfer and equilibrium","volume":"14","author":"Galano","year":"2012","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/S1074-5521(98)90619-6","article-title":"DNA damage induced via independent generation of the radical resulting from formal hydrogen atom abstraction from the C1\u2019-position of a nucleotide","volume":"5","author":"Tronche","year":"1998","journal-title":"Chem. Biol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1021\/cr960437i","article-title":"Oxidative Strand Scission of Nucleic Acids:\u2009 Routes Initiated by Hydrogen Abstraction from the Sugar Moiety","volume":"98","author":"Pogozelski","year":"1998","journal-title":"Chem. Rev."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1021\/tx700283c","article-title":"The Chemical Toxicology of 2-Deoxyribose Oxidation in DNA","volume":"21","author":"Dedon","year":"2007","journal-title":"Chem. Res. Toxicol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1021\/acs.chemrestox.6b00265","article-title":"Occurrence, Biological Consequences, and Human Health Relevance of Oxidative Stress-Induced DNA Damage","volume":"29","author":"Yu","year":"2016","journal-title":"Chem. Res. Toxicol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1080\/10590500902885684","article-title":"8-Hydroxy-2\u2032 -deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress and carcinogenesis","volume":"27","author":"Valavanidis","year":"2009","journal-title":"J. Environ. Sci. Health C Environ. Carcinog. Ecotoxicol. Rev."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"CR329","DOI":"10.12659\/MSM.881805","article-title":"Oxidative damage DNA: 8-oxogua and 8-oxodG as molecular markers of cancer","volume":"17","author":"Roszkowski","year":"2011","journal-title":"Med. Sci. Monit."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"e12539","DOI":"10.1111\/jpi.12539","article-title":"Melatonin and its metabolites as chemical agents capable of directly repairing oxidized DNA","volume":"66","author":"Reiter","year":"2019","journal-title":"J. Pineal Res."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/s00214-020-02641-9","article-title":"Computer-designed melatonin derivatives: Potent peroxyl radical scavengers with no pro-oxidant behavior","volume":"139","author":"Reina","year":"2020","journal-title":"Theor. Chem. Acc."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"9566","DOI":"10.1021\/acsomega.0c00898","article-title":"Computationally Designed Sesamol Derivatives Proposed as Potent Antioxidants","volume":"5","author":"Galano","year":"2020","journal-title":"ACS Omega"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"11960","DOI":"10.1039\/D1NJ02225C","article-title":"Free radical scavenging activity of newly designed sesamol derivatives","volume":"45","author":"Galano","year":"2021","journal-title":"New J. Chem."},{"key":"ref_150","doi-asserted-by":"crossref","unstructured":"Galano, A., Guzm\u00e1n-L\u00f3pez, E.G., and Reiter, R.J. (2021). Potentiating the benefits of melatonin through chemical functionalization: Possible impact on multifactorial neurodegenerative disorders. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111584"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s00214-022-02907-4","article-title":"Newly designed melatonin analogues with potential neuroprotective effects","volume":"141","author":"Serratos","year":"2022","journal-title":"Theor. Chem. Acc."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"14369","DOI":"10.1039\/D1NJ01235E","article-title":"Computationally designed: P -coumaric acid analogs: Searching for neuroprotective antioxidants","volume":"45","author":"Reina","year":"2021","journal-title":"New J. Chem."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"27","DOI":"10.32794\/mr11250003","article-title":"A Computer-Assisted Systematic Search for Melatonin Derivatives with High Potential as Antioxidants","volume":"1","author":"Reina","year":"2018","journal-title":"Melatonin Res."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"7178","DOI":"10.1039\/c0cp02801k","article-title":"On the direct scavenging activity of melatonin towards hydroxyl and a series of peroxyl radicals","volume":"13","author":"Galano","year":"2011","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"4642","DOI":"10.1039\/c3cp43319f","article-title":"A physicochemical examination of the free radical scavenging activity of Trolox: Mechanism, kinetics and influence of the environment","volume":"15","author":"Alberto","year":"2013","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1073\/pnas.90.1.45","article-title":"Autoxidation of lipids and antioxidation by a-tocopherol and ubiquinol in homogeneous solution and in aqueous dispersions of lipids: Unrecognized consequences of lipid particle size as exemplified by oxidation of human low density lipoprotein","volume":"90","author":"Ingold","year":"1993","journal-title":"Proc. Nati. Acad. Sci. USA"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1063\/1.555739","article-title":"Reactivity of HO2\/O\u22122 radicals in aqueous solution","volume":"14","author":"Bielski","year":"1985","journal-title":"J. Phys. Chem. Ref. Data"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1111\/jpi.12196","article-title":"Melatonin and its metabolites as copper chelating agents and their role in inhibiting oxidative stress: A physicochemical analysis","volume":"58","author":"Galano","year":"2015","journal-title":"J. Pineal Res."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"9559","DOI":"10.1021\/jp904816d","article-title":"Computational Study of Copper(II) Complexation and Hydrolysis in Aqueous Solutions Using Mixed Cluster\/Continuum Models","volume":"113","author":"Bryantsev","year":"2009","journal-title":"J. Phys. Chem. A"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"8070","DOI":"10.1021\/jm0580454","article-title":"Synthesis and Biological Evaluation of a Novel Series of \u201cOrtho-Nitrated\u201d Inhibitors of Catechol-O-methyltransferase","volume":"48","author":"Learmonth","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"17640","DOI":"10.1016\/S0021-9258(19)37091-7","article-title":"Mutagenesis of human acetylcholinesterase. Identification of residues involved in catalytic activity and in polypeptide folding","volume":"267","author":"Shafferman","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.phrs.2008.08.001","article-title":"Inhibition of acetylcholinesterase by coumarins: The case of coumarin 106","volume":"58","author":"Fallarero","year":"2008","journal-title":"Pharmacol. Res."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"5848","DOI":"10.1021\/jm070677y","article-title":"Structures of Human Monoamine Oxidase B Complexes with Selective Noncovalent Inhibitors:\u2009 Safinamide and Coumarin Analogs","volume":"50","author":"Binda","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"10282","DOI":"10.1021\/jm300871x","article-title":"Structures of human acetylcholinesterase in complex with pharmacologically important ligands","volume":"55","author":"Cheung","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.ejpn.2021.02.003","article-title":"Melatonin for neuroprotection in neonatal encephalopathy: A systematic review & meta-analysis of clinical trials","volume":"31","author":"Ahmed","year":"2021","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1002\/jnr.24220","article-title":"The neuroprotective role of melatonin in neurological disorders","volume":"96","author":"Alghamdi","year":"2018","journal-title":"J. Neurosci. Res."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.3233\/JAD-170900","article-title":"Multi-Faceted Role of Melatonin in Neuroprotection and Amelioration of Tau Aggregates in Alzheimer\u2019s Disease","volume":"62","author":"Balmik","year":"2018","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/s41398-021-01464-x","article-title":"Melatonin\u2019s neuroprotective role in mitochondria and its potential as a biomarker in aging, cognition and psychiatric disorders","volume":"11","author":"Brown","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"ref_169","unstructured":"(2022, March 03). Calculation of Molecular Properties and Bioactivity Score. Available online: https:\/\/www.molinspiration.com\/cgi-bin\/properties."},{"key":"ref_170","unstructured":"(2020, February 08). Drug Likeness Tool (DruLiTo 1), Available online: http:\/\/www.niper.gov.in\/pi_dev_tools\/DruLiToWeb\/DruLiTo_index.html."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1021\/ci700443v","article-title":"Combinatorial QSAR Modeling of Chemical Toxicants Tested against Tetrahymena pyriformis","volume":"48","author":"Zhu","year":"2008","journal-title":"J. Chem. Inf. Model."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1007\/s10822-006-9099-2","article-title":"Structure and reaction based evaluation of synthetic accessibility","volume":"21","author":"Boda","year":"2007","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.ejmech.2012.06.024","article-title":"Is chemical synthetic accessibility computationally predictable for drug and lead-like molecules? A comparative assessment between medicinal and computational chemists","volume":"54","author":"Bonnet","year":"2012","journal-title":"Eur. J. Med. Chem."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"6378","DOI":"10.1021\/jp810292n","article-title":"Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions","volume":"113","author":"Marenich","year":"2009","journal-title":"J. Phys. Chem. B"},{"key":"ref_175","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Petersson, G.A., and Nakatsuji, H. (2016). Gaussian 16 Rev. C.01, Gaussian Inc."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1107\/S0907444912001138","article-title":"Catechol-O-methyltransferase in complex with substituted 3\u2019-deoxyribose bisubstrate inhibitors","volume":"68","author":"Ellermann","year":"2012","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera--a visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_179","unstructured":"(2022, September 10). BIOVIA. Available online: https:\/\/www.3ds.com\/products-services\/biovia\/."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/21\/13246\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:06:32Z","timestamp":1760144792000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/21\/13246"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,31]]},"references-count":179,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232113246"],"URL":"https:\/\/doi.org\/10.3390\/ijms232113246","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,31]]}}}