Identification of a Novel Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase: In Vitro and In Silico Studies
The enhancement of cholinergic functions via acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition is considered a valuable therapeutic strategy for the treatment of Alzheimer’s disease. This study aimed to evaluate the in vitro effect of ZINC390718, previously filtered using comp...
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MDPI AG
2023-01-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/1/95 |
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| author | Raquel B. M. de Almeida Deyse B. Barbosa Mayra R. do Bomfim Jéssika A. O. Amparo Bruno S. Andrade Silvia L. Costa Joaquín M. Campos Jorddy N. Cruz Cleydson B. R. Santos Franco H. A. Leite Mariana B. Botura |
| author_facet | Raquel B. M. de Almeida Deyse B. Barbosa Mayra R. do Bomfim Jéssika A. O. Amparo Bruno S. Andrade Silvia L. Costa Joaquín M. Campos Jorddy N. Cruz Cleydson B. R. Santos Franco H. A. Leite Mariana B. Botura |
| author_sort | Raquel B. M. de Almeida |
| collection | DOAJ |
| description | The enhancement of cholinergic functions via acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition is considered a valuable therapeutic strategy for the treatment of Alzheimer’s disease. This study aimed to evaluate the in vitro effect of ZINC390718, previously filtered using computational approaches, on both cholinesterases and to characterize, using a molecular dynamics (MD) simulation, the possible binding mode of this compound inside the cholinesterase enzymes. The in vitro cytotoxicity effect was also investigated using a primary astrocyte-enriched glial cell culture. ZINC390718 presented in vitro dual inhibitory activity against AChE at a high micromolar range (IC<sub>50</sub> = 543.8 µM) and against BuChE (IC<sub>50</sub> = 241.1 µM) in a concentration-dependent manner, with greater activity against BuChE. The MD simulation revealed that ZINC390718 performed important hydrophobic and H-bond interactions with the catalytic residue sites on both targets. The residues that promoted the hydrophobic interactions and H-bonding in the AChE target were Leu67, Trp86, Phe123, Tyr124, Ser293, Phe295, and Tyr341, and on the BuChE target, they were Asp70, Tyr332, Tyr128, Ile442, Trp82, and Glu197. The cytotoxic effect of Z390718, evaluated via cell viability, showed that the molecule has low in vitro toxicity. The in vitro and in silico results indicate that ZINC390718 can be used as chemotype for the optimization and identification of new dual cholinesterase inhibitors. |
| first_indexed | 2024-03-09T11:28:30Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T11:28:30Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
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| series | Pharmaceuticals |
| spelling | doaj.art-6e346028fd874c07af33ade6de3f30a12023-11-30T23:55:44ZengMDPI AGPharmaceuticals1424-82472023-01-011619510.3390/ph16010095Identification of a Novel Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase: In Vitro and In Silico StudiesRaquel B. M. de Almeida0Deyse B. Barbosa1Mayra R. do Bomfim2Jéssika A. O. Amparo3Bruno S. Andrade4Silvia L. Costa5Joaquín M. Campos6Jorddy N. Cruz7Cleydson B. R. Santos8Franco H. A. Leite9Mariana B. Botura10Department of Health, State University of Feira de Santana, Feira de Santana 44036-900, BA, BrazilDepartment of Health, State University of Feira de Santana, Feira de Santana 44036-900, BA, BrazilDepartment of Health, State University of Feira de Santana, Feira de Santana 44036-900, BA, BrazilInstitute of Health Sciences, Federal University of Bahia, Salvador 40170-110, BA, BrazilDepartment of Biological Sciences, State University of Southwest of Bahia, Jequié 45208-091, BA, BrazilInstitute of Health Sciences, Federal University of Bahia, Salvador 40170-110, BA, BrazilBiosanitary Institute of Granada (ibs.GRANADA), University of Granada, 18071 Granada, SpainLaboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, AP, BrazilDepartment of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Campus of Cartuja, University of Granada, 18071 Granada, SpainDepartment of Health, State University of Feira de Santana, Feira de Santana 44036-900, BA, BrazilDepartment of Health, State University of Feira de Santana, Feira de Santana 44036-900, BA, BrazilThe enhancement of cholinergic functions via acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition is considered a valuable therapeutic strategy for the treatment of Alzheimer’s disease. This study aimed to evaluate the in vitro effect of ZINC390718, previously filtered using computational approaches, on both cholinesterases and to characterize, using a molecular dynamics (MD) simulation, the possible binding mode of this compound inside the cholinesterase enzymes. The in vitro cytotoxicity effect was also investigated using a primary astrocyte-enriched glial cell culture. ZINC390718 presented in vitro dual inhibitory activity against AChE at a high micromolar range (IC<sub>50</sub> = 543.8 µM) and against BuChE (IC<sub>50</sub> = 241.1 µM) in a concentration-dependent manner, with greater activity against BuChE. The MD simulation revealed that ZINC390718 performed important hydrophobic and H-bond interactions with the catalytic residue sites on both targets. The residues that promoted the hydrophobic interactions and H-bonding in the AChE target were Leu67, Trp86, Phe123, Tyr124, Ser293, Phe295, and Tyr341, and on the BuChE target, they were Asp70, Tyr332, Tyr128, Ile442, Trp82, and Glu197. The cytotoxic effect of Z390718, evaluated via cell viability, showed that the molecule has low in vitro toxicity. The in vitro and in silico results indicate that ZINC390718 can be used as chemotype for the optimization and identification of new dual cholinesterase inhibitors.https://www.mdpi.com/1424-8247/16/1/95Alzheimer’s diseaseacetylcholinesterasebutyrylcholinesteraseinhibitors |
| spellingShingle | Raquel B. M. de Almeida Deyse B. Barbosa Mayra R. do Bomfim Jéssika A. O. Amparo Bruno S. Andrade Silvia L. Costa Joaquín M. Campos Jorddy N. Cruz Cleydson B. R. Santos Franco H. A. Leite Mariana B. Botura Identification of a Novel Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase: In Vitro and In Silico Studies Pharmaceuticals Alzheimer’s disease acetylcholinesterase butyrylcholinesterase inhibitors |
| title | Identification of a Novel Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase: In Vitro and In Silico Studies |
| title_full | Identification of a Novel Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase: In Vitro and In Silico Studies |
| title_fullStr | Identification of a Novel Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase: In Vitro and In Silico Studies |
| title_full_unstemmed | Identification of a Novel Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase: In Vitro and In Silico Studies |
| title_short | Identification of a Novel Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase: In Vitro and In Silico Studies |
| title_sort | identification of a novel dual inhibitor of acetylcholinesterase and butyrylcholinesterase in vitro and in silico studies |
| topic | Alzheimer’s disease acetylcholinesterase butyrylcholinesterase inhibitors |
| url | https://www.mdpi.com/1424-8247/16/1/95 |
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