Development of Potential Multi-Target Inhibitors for Human Cholinesterases and Beta-Secretase 1: A Computational Approach
Alzheimer’s disease causes chronic neurodegeneration and is the leading cause of dementia in the world. The causes of this disease are not fully understood but seem to involve two essential cerebral pathways: cholinergic and amyloid. The simultaneous inhibition of AChE, BuChE, and BACE-1, essential...
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| Format: | Article |
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MDPI AG
2023-11-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/12/1657 |
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| author | Deyse B. Barbosa Mayra R. do Bomfim Tiago A. de Oliveira Alisson M. da Silva Alex G. Taranto Jorddy N. Cruz Paulo B. de Carvalho Joaquín M. Campos Cleydson B. R. Santos Franco H. A. Leite |
| author_facet | Deyse B. Barbosa Mayra R. do Bomfim Tiago A. de Oliveira Alisson M. da Silva Alex G. Taranto Jorddy N. Cruz Paulo B. de Carvalho Joaquín M. Campos Cleydson B. R. Santos Franco H. A. Leite |
| author_sort | Deyse B. Barbosa |
| collection | DOAJ |
| description | Alzheimer’s disease causes chronic neurodegeneration and is the leading cause of dementia in the world. The causes of this disease are not fully understood but seem to involve two essential cerebral pathways: cholinergic and amyloid. The simultaneous inhibition of AChE, BuChE, and BACE-1, essential enzymes involved in those pathways, is a promising therapeutic approach to treat the symptoms and, hopefully, also halt the disease progression. This study sought to identify triple enzymatic inhibitors based on stereo-electronic requirements deduced from molecular modeling of AChE, BuChE, and BACE-1 active sites. A pharmacophore model was built, displaying four hydrophobic centers, three hydrogen bond acceptors, and one positively charged nitrogen, and used to prioritize molecules found in virtual libraries. Compounds showing adequate overlapping rates with the pharmacophore were subjected to molecular docking against the three enzymes and those with an adequate docking score (<i>n</i> = 12) were evaluated for physicochemical and toxicological parameters and commercial availability. The structure exhibiting the greatest inhibitory potential against all three enzymes was subjected to molecular dynamics simulations (100 ns) to assess the stability of the inhibitor-enzyme systems. The results of this in silico approach indicate ZINC1733 can be a potential multi-target inhibitor of AChE, BuChE, and BACE-1, and future enzymatic assays are planned to validate those results. |
| first_indexed | 2024-03-08T20:27:37Z |
| format | Article |
| id | doaj.art-fdd4fbc549674dd0b53eb8d1d2cef958 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-08T20:27:37Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-fdd4fbc549674dd0b53eb8d1d2cef9582023-12-22T14:31:20ZengMDPI AGPharmaceuticals1424-82472023-11-011612165710.3390/ph16121657Development of Potential Multi-Target Inhibitors for Human Cholinesterases and Beta-Secretase 1: A Computational ApproachDeyse B. Barbosa0Mayra R. do Bomfim1Tiago A. de Oliveira2Alisson M. da Silva3Alex G. Taranto4Jorddy N. Cruz5Paulo B. de Carvalho6Joaquín M. Campos7Cleydson B. R. Santos8Franco H. A. Leite9Laboratório de Modelagem Molecular, Departamento de Saúde, Universidade Estadual de Feira de Santana, Feira de Santana 44036-900, BA, BrazilLaboratório de Modelagem Molecular, Departamento de Saúde, Universidade Estadual de Feira de Santana, Feira de Santana 44036-900, BA, BrazilDepartamento de Informática, Gestão e Desenho, Centro Federal de Educação Tecnológica de Minas Gerais, Divinópolis 30575-180, MG, BrazilLaboratório de Bioinformática e Desenho de Fármacos, Universidade Federal de São João del-Rei, São João del-Rei 36307-352, MG, BrazilLaboratório de Bioinformática e Desenho de Fármacos, Universidade Federal de São João del-Rei, São João del-Rei 36307-352, MG, BrazilLaboratório de Modelagem e Química Computacional, Departamento de Ciências Biológicas e de Saúde, Universidade Federal do Amapá, Macapá 68903-419, AP, BrazilFeik School of Pharmacy, University of the Incarnate Word, San Antonio, TX 78209, USADepartamento de Química Orgánica Farmacéutica, Facultad de Farmacia, Campus de la Cartuja, Universidad de Granada, 18012 Granada, SpainLaboratório de Modelagem e Química Computacional, Departamento de Ciências Biológicas e de Saúde, Universidade Federal do Amapá, Macapá 68903-419, AP, BrazilLaboratório de Modelagem Molecular, Departamento de Saúde, Universidade Estadual de Feira de Santana, Feira de Santana 44036-900, BA, BrazilAlzheimer’s disease causes chronic neurodegeneration and is the leading cause of dementia in the world. The causes of this disease are not fully understood but seem to involve two essential cerebral pathways: cholinergic and amyloid. The simultaneous inhibition of AChE, BuChE, and BACE-1, essential enzymes involved in those pathways, is a promising therapeutic approach to treat the symptoms and, hopefully, also halt the disease progression. This study sought to identify triple enzymatic inhibitors based on stereo-electronic requirements deduced from molecular modeling of AChE, BuChE, and BACE-1 active sites. A pharmacophore model was built, displaying four hydrophobic centers, three hydrogen bond acceptors, and one positively charged nitrogen, and used to prioritize molecules found in virtual libraries. Compounds showing adequate overlapping rates with the pharmacophore were subjected to molecular docking against the three enzymes and those with an adequate docking score (<i>n</i> = 12) were evaluated for physicochemical and toxicological parameters and commercial availability. The structure exhibiting the greatest inhibitory potential against all three enzymes was subjected to molecular dynamics simulations (100 ns) to assess the stability of the inhibitor-enzyme systems. The results of this in silico approach indicate ZINC1733 can be a potential multi-target inhibitor of AChE, BuChE, and BACE-1, and future enzymatic assays are planned to validate those results.https://www.mdpi.com/1424-8247/16/12/1657Alzheimer’s diseasemolecular dockingmolecular dynamicspharmacophore modeltriple inhibitors |
| spellingShingle | Deyse B. Barbosa Mayra R. do Bomfim Tiago A. de Oliveira Alisson M. da Silva Alex G. Taranto Jorddy N. Cruz Paulo B. de Carvalho Joaquín M. Campos Cleydson B. R. Santos Franco H. A. Leite Development of Potential Multi-Target Inhibitors for Human Cholinesterases and Beta-Secretase 1: A Computational Approach Pharmaceuticals Alzheimer’s disease molecular docking molecular dynamics pharmacophore model triple inhibitors |
| title | Development of Potential Multi-Target Inhibitors for Human Cholinesterases and Beta-Secretase 1: A Computational Approach |
| title_full | Development of Potential Multi-Target Inhibitors for Human Cholinesterases and Beta-Secretase 1: A Computational Approach |
| title_fullStr | Development of Potential Multi-Target Inhibitors for Human Cholinesterases and Beta-Secretase 1: A Computational Approach |
| title_full_unstemmed | Development of Potential Multi-Target Inhibitors for Human Cholinesterases and Beta-Secretase 1: A Computational Approach |
| title_short | Development of Potential Multi-Target Inhibitors for Human Cholinesterases and Beta-Secretase 1: A Computational Approach |
| title_sort | development of potential multi target inhibitors for human cholinesterases and beta secretase 1 a computational approach |
| topic | Alzheimer’s disease molecular docking molecular dynamics pharmacophore model triple inhibitors |
| url | https://www.mdpi.com/1424-8247/16/12/1657 |
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