Molecular Multi-Target Approach for Human Acetylcholinesterase, Butyrylcholinesterase and <i>β</i>-Secretase 1: Next Generation for Alzheimer’s Disease Treatment
Alzheimer’s Disease (AD) is a neurodegenerative condition characterized by progressive memory loss and other affected cognitive functions. Pharmacological therapy of AD relies on inhibitors of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), offering only a palliative effect...
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| Format: | Article |
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MDPI AG
2023-06-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/6/880 |
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| author | Géssica Oliveira Mendes Samuel Silva da Rocha Pita Paulo Batista de Carvalho Michel Pires da Silva Alex Gutterres Taranto Franco Henrique Andrade Leite |
| author_facet | Géssica Oliveira Mendes Samuel Silva da Rocha Pita Paulo Batista de Carvalho Michel Pires da Silva Alex Gutterres Taranto Franco Henrique Andrade Leite |
| author_sort | Géssica Oliveira Mendes |
| collection | DOAJ |
| description | Alzheimer’s Disease (AD) is a neurodegenerative condition characterized by progressive memory loss and other affected cognitive functions. 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 <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>-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. |
| first_indexed | 2024-03-11T02:03:12Z |
| format | Article |
| id | doaj.art-6c0d5eb7386544ac830fa9adc5d1a850 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-11T02:03:12Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-6c0d5eb7386544ac830fa9adc5d1a8502023-11-18T12:02:51ZengMDPI AGPharmaceuticals1424-82472023-06-0116688010.3390/ph16060880Molecular Multi-Target Approach for Human Acetylcholinesterase, Butyrylcholinesterase and <i>β</i>-Secretase 1: Next Generation for Alzheimer’s Disease TreatmentGéssica Oliveira Mendes0Samuel Silva da Rocha Pita1Paulo Batista de Carvalho2Michel Pires da Silva3Alex Gutterres Taranto4Franco Henrique Andrade Leite5Laboratory of Molecular Modeling, Department of Health, State University of Feira de Santana, Salvador 44036-900, BA, BrazilPostgraduate Program in Pharmaceutical Sciences, State University of Feira de Santana, Salvador 44036-900, BA, BrazilFeik School of Pharmacy, University of the Incarnate Word, San Antonio, TX 78212, USALaboratory of Bioinformatics and Drug Design, Department of Bioengineering, Federal University of Sao Joao del-Rei, São João del-Rei 36301-1601, MG, BrazilLaboratory of Bioinformatics and Drug Design, Department of Bioengineering, Federal University of Sao Joao del-Rei, São João del-Rei 36301-1601, MG, BrazilLaboratory of Molecular Modeling, Department of Health, State University of Feira de Santana, Salvador 44036-900, BA, BrazilAlzheimer’s Disease (AD) is a neurodegenerative condition characterized by progressive memory loss and other affected cognitive functions. 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 <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>-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.https://www.mdpi.com/1424-8247/16/6/880molecular hybridsAlzheimer’s diseasecholinesterasehuman <i>β</i>-secretase 1molecular dynamics |
| spellingShingle | Géssica Oliveira Mendes Samuel Silva da Rocha Pita Paulo Batista de Carvalho Michel Pires da Silva Alex Gutterres Taranto Franco Henrique Andrade Leite Molecular Multi-Target Approach for Human Acetylcholinesterase, Butyrylcholinesterase and <i>β</i>-Secretase 1: Next Generation for Alzheimer’s Disease Treatment Pharmaceuticals molecular hybrids Alzheimer’s disease cholinesterase human <i>β</i>-secretase 1 molecular dynamics |
| title | Molecular Multi-Target Approach for Human Acetylcholinesterase, Butyrylcholinesterase and <i>β</i>-Secretase 1: Next Generation for Alzheimer’s Disease Treatment |
| title_full | Molecular Multi-Target Approach for Human Acetylcholinesterase, Butyrylcholinesterase and <i>β</i>-Secretase 1: Next Generation for Alzheimer’s Disease Treatment |
| title_fullStr | Molecular Multi-Target Approach for Human Acetylcholinesterase, Butyrylcholinesterase and <i>β</i>-Secretase 1: Next Generation for Alzheimer’s Disease Treatment |
| title_full_unstemmed | Molecular Multi-Target Approach for Human Acetylcholinesterase, Butyrylcholinesterase and <i>β</i>-Secretase 1: Next Generation for Alzheimer’s Disease Treatment |
| title_short | Molecular Multi-Target Approach for Human Acetylcholinesterase, Butyrylcholinesterase and <i>β</i>-Secretase 1: Next Generation for Alzheimer’s Disease Treatment |
| title_sort | molecular multi target approach for human acetylcholinesterase butyrylcholinesterase and i β i secretase 1 next generation for alzheimer s disease treatment |
| topic | molecular hybrids Alzheimer’s disease cholinesterase human <i>β</i>-secretase 1 molecular dynamics |
| url | https://www.mdpi.com/1424-8247/16/6/880 |
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