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Pharmacological therapy of AD relies on inhibitors of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), offering only a palliative effect and being incapable of stopping or reversing the neurodegenerative process. However, recent studies have shown that inhibiting the enzyme \u03b2-secretase 1 (BACE-1) may be able to stop neurodegeneration, making it a promising target. Considering these three enzymatic targets, it becomes feasible to apply computational techniques to guide the identification and planning of molecules capable of binding to all of them. After virtually screening 2119 molecules from a library, 13 hybrids were built and further screened by triple pharmacophoric model, molecular docking, and molecular dynamics (t = 200 ns). The selected hybrid G meets all stereo-electronic requirements to bind to AChE, BChE, and BACE-1 and offers a promising structure for future synthesis, enzymatic testing, and validation.<\/jats:p>","DOI":"10.3390\/ph16060880","type":"journal-article","created":{"date-parts":[[2023,6,15]],"date-time":"2023-06-15T02:28:56Z","timestamp":1686796136000},"page":"880","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Molecular Multi-Target Approach for Human Acetylcholinesterase, Butyrylcholinesterase and \u03b2-Secretase 1: Next Generation for Alzheimer\u2019s Disease Treatment"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4543-3144","authenticated-orcid":false,"given":"G\u00e9ssica Oliveira","family":"Mendes","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Modeling, Department of Health, State University of Feira de Santana, Salvador 44036-900, BA, Brazil"},{"name":"Postgraduate Program in Pharmaceutical Sciences, State University of Feira de Santana, Salvador 44036-900, BA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4053-8721","authenticated-orcid":false,"given":"Samuel Silva da Rocha","family":"Pita","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Pharmaceutical Sciences, State University of Feira de Santana, Salvador 44036-900, BA, Brazil"},{"name":"Laboratory of Bioinformatics and Molecular Modeling (LaBiMM), Pharmacy College, Federal University of Bahia (UFBA), Salvador 40170-110, BA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8251-9214","authenticated-orcid":false,"given":"Paulo Batista de","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Feik School of Pharmacy, University of the Incarnate Word, San Antonio, TX 78212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1343-1331","authenticated-orcid":false,"given":"Michel Pires da","family":"Silva","sequence":"additional","affiliation":[{"name":"Laboratory of Bioinformatics and Drug Design, Department of Bioengineering, Federal University of Sao Joao del-Rei, S\u00e3o Jo\u00e3o del-Rei 36301-1601, MG, Brazil"},{"name":"Federal Center for Technological Education of Minas Gerais, Department of Informatics, Management and Design, R. \u00c1lvares de Azevedo, 400, Bela Vista, Divin\u00f3polis 35503-822, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6086-1043","authenticated-orcid":false,"given":"Alex Gutterres","family":"Taranto","sequence":"additional","affiliation":[{"name":"Laboratory of Bioinformatics and Drug Design, Department of Bioengineering, Federal University of Sao Joao del-Rei, S\u00e3o Jo\u00e3o del-Rei 36301-1601, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3166-6051","authenticated-orcid":false,"given":"Franco Henrique Andrade","family":"Leite","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Modeling, Department of Health, State University of Feira de Santana, Salvador 44036-900, BA, Brazil"},{"name":"Postgraduate Program in Pharmaceutical Sciences, State University of Feira de Santana, Salvador 44036-900, BA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1186\/s13065-018-0497-z","article-title":"Molecular docking studies of coumarin hybrids as potential acetylcholinesterase, butyrylcholinesterase, monoamine oxidase A\/B and \u03b2-amyloid inhibitors for Alzheimer\u2019s disease","volume":"12","author":"Yusufzai","year":"2018","journal-title":"Chem. 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