Galantamine Based Novel Acetylcholinesterase Enzyme Inhibitors: A Molecular Modeling Design Approach
Acetylcholinesterase (AChE) enzymes play an essential role in the development of Alzheimer’s disease (AD). Its excessive activity causes several neuronal problems, particularly psychopathies and neuronal cell death. A bioactive pose on the <i>h</i>AChE B site of the human acetylcholinest...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/3/1035 |
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| author | Luciane B. Silva Elenilze F. B. Ferreira Maryam José M. Espejo-Román Glauber V. Costa Josiane V. Cruz Njogu M. Kimani Josivan S. Costa José A. H. M. Bittencourt Jorddy N. Cruz Joaquín M. Campos Cleydson B. R. Santos |
| author_facet | Luciane B. Silva Elenilze F. B. Ferreira Maryam José M. Espejo-Román Glauber V. Costa Josiane V. Cruz Njogu M. Kimani Josivan S. Costa José A. H. M. Bittencourt Jorddy N. Cruz Joaquín M. Campos Cleydson B. R. Santos |
| author_sort | Luciane B. Silva |
| collection | DOAJ |
| description | Acetylcholinesterase (AChE) enzymes play an essential role in the development of Alzheimer’s disease (AD). Its excessive activity causes several neuronal problems, particularly psychopathies and neuronal cell death. A bioactive pose on the <i>h</i>AChE B site of the human acetylcholinesterase (<i>h</i>AChE) enzyme employed in this investigation, which was obtained from the Protein Data Bank (PDB ID 4EY6), allowed for the prediction of the binding affinity and free binding energy between the protein and the ligand. Virtual screening was performed to obtain structures similar to Galantamine (GNT) with potential <i>h</i>AChE activity. The top 200 hit compounds were prioritized through the use of filters in ZincPharmer, with special features related to the pharmacophore. Critical analyses were carried out, such as hierarchical clustering analysis (HCA), ADME/Tox predictions, molecular docking, molecular simulation studies, synthetic accessibility (SA), lipophilicity, water solubility, and hot spots to confirm the stable binding of the two promising molecules (ZINC16951574-LMQC2, and ZINC08342556-LMQC5). The metabolism prediction, with metabolites M3-2, which is formed by Glutathionation reaction (Phase II), M1-2, and M2-2 formed from the reaction of S-oxidation and Aliphatic hydroxylation (Phase I), were both reactive but with no side effects. Theoretical synthetic routes and prediction of synthetic accessibility for the most promising compounds are also proposed. In conclusion, this study shows that in silico modeling can be used to create new drug candidate inhibitors for <i>h</i>AChE. The compounds ZINC16951574-LMQC2, and ZINC08342556-LMQC5 are particularly promising for oral administration because they have a favorable drug-likeness profile, excellent lipid solubility, high bioavailability, and adequate pharmacokinetics. |
| first_indexed | 2024-03-11T09:33:46Z |
| format | Article |
| id | doaj.art-dc71a5ccb35141a8b7192fc4f562a8a2 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T09:33:46Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-dc71a5ccb35141a8b7192fc4f562a8a22023-11-16T17:26:44ZengMDPI AGMolecules1420-30492023-01-01283103510.3390/molecules28031035Galantamine Based Novel Acetylcholinesterase Enzyme Inhibitors: A Molecular Modeling Design ApproachLuciane B. Silva0Elenilze F. B. Ferreira1Maryam2José M. Espejo-Román3Glauber V. Costa4Josiane V. Cruz5Njogu M. Kimani6Josivan S. Costa7José A. H. M. Bittencourt8Jorddy N. Cruz9Joaquín M. Campos10Cleydson B. R. Santos11Graduate Program in Medicinal Chemistry and Molecular Modeling, Health Science Institute, Federal University of Pará, Belém 66075-110, BrazilLaboratory of Organic Chemistry and Biochemistry, University of the State of Amapá, Macapá 68900-070, BrazilCOMSATS University Islamabad, Park Road, Tarlai Kalan, Islamabad 45550, PakistanDepartment of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Campus of Cartuja, University of Granada, 18071 Granada, SpainLaboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, BrazilLaboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, BrazilDepartment of Physical Sciences, University of Embu, Embu P.O. Box 6-60100, KenyaLaboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, BrazilLaboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, BrazilLaboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, BrazilDepartment of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Campus of Cartuja, University of Granada, 18071 Granada, SpainGraduate Program in Medicinal Chemistry and Molecular Modeling, Health Science Institute, Federal University of Pará, Belém 66075-110, BrazilAcetylcholinesterase (AChE) enzymes play an essential role in the development of Alzheimer’s disease (AD). Its excessive activity causes several neuronal problems, particularly psychopathies and neuronal cell death. A bioactive pose on the <i>h</i>AChE B site of the human acetylcholinesterase (<i>h</i>AChE) enzyme employed in this investigation, which was obtained from the Protein Data Bank (PDB ID 4EY6), allowed for the prediction of the binding affinity and free binding energy between the protein and the ligand. Virtual screening was performed to obtain structures similar to Galantamine (GNT) with potential <i>h</i>AChE activity. The top 200 hit compounds were prioritized through the use of filters in ZincPharmer, with special features related to the pharmacophore. Critical analyses were carried out, such as hierarchical clustering analysis (HCA), ADME/Tox predictions, molecular docking, molecular simulation studies, synthetic accessibility (SA), lipophilicity, water solubility, and hot spots to confirm the stable binding of the two promising molecules (ZINC16951574-LMQC2, and ZINC08342556-LMQC5). The metabolism prediction, with metabolites M3-2, which is formed by Glutathionation reaction (Phase II), M1-2, and M2-2 formed from the reaction of S-oxidation and Aliphatic hydroxylation (Phase I), were both reactive but with no side effects. Theoretical synthetic routes and prediction of synthetic accessibility for the most promising compounds are also proposed. In conclusion, this study shows that in silico modeling can be used to create new drug candidate inhibitors for <i>h</i>AChE. The compounds ZINC16951574-LMQC2, and ZINC08342556-LMQC5 are particularly promising for oral administration because they have a favorable drug-likeness profile, excellent lipid solubility, high bioavailability, and adequate pharmacokinetics.https://www.mdpi.com/1420-3049/28/3/1035Alzheimer’s diseaseADMEmolecular docking and molecular dynamics |
| spellingShingle | Luciane B. Silva Elenilze F. B. Ferreira Maryam José M. Espejo-Román Glauber V. Costa Josiane V. Cruz Njogu M. Kimani Josivan S. Costa José A. H. M. Bittencourt Jorddy N. Cruz Joaquín M. Campos Cleydson B. R. Santos Galantamine Based Novel Acetylcholinesterase Enzyme Inhibitors: A Molecular Modeling Design Approach Molecules Alzheimer’s disease ADME molecular docking and molecular dynamics |
| title | Galantamine Based Novel Acetylcholinesterase Enzyme Inhibitors: A Molecular Modeling Design Approach |
| title_full | Galantamine Based Novel Acetylcholinesterase Enzyme Inhibitors: A Molecular Modeling Design Approach |
| title_fullStr | Galantamine Based Novel Acetylcholinesterase Enzyme Inhibitors: A Molecular Modeling Design Approach |
| title_full_unstemmed | Galantamine Based Novel Acetylcholinesterase Enzyme Inhibitors: A Molecular Modeling Design Approach |
| title_short | Galantamine Based Novel Acetylcholinesterase Enzyme Inhibitors: A Molecular Modeling Design Approach |
| title_sort | galantamine based novel acetylcholinesterase enzyme inhibitors a molecular modeling design approach |
| topic | Alzheimer’s disease ADME molecular docking and molecular dynamics |
| url | https://www.mdpi.com/1420-3049/28/3/1035 |
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