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Computational identification of promising therapeutics via BACE1 Targeting: Implications for Alzheimer's disease.
Murad, Hussam Aly Sayed; Moawadh, Mamdoh S; Alzahrani, Abdulrahman; Alkathiri, Ahmad Salah; Almutairi, Abdulrahman; Alhassoun, Madawi Ibrahim; Alniwaider, Rashed Ahmed; Habib, Alaa Hamed; Sain, Ziaullah M.
Afiliação
  • Murad HAS; Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, Saudi Arabia. hamurad@kau.edu.sa.
  • Moawadh MS; Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk Saudi Arabia. mmoawadh@ut.edu.sa.
  • Alzahrani A; Department of Applied Medical Sciences, Applied College, Al-Baha University, Al-Baha City, Kingdom of Saudi. abdulrahmanmuidh@gmail.com.
  • Alkathiri AS; Department of Health Promotion and Education, Faculty of Public Health & Health Informatics, Umm Al-Qura University, Makkah, Kingdom of Saudi Arabia. asskathiri@uqu.edu.sa.
  • Almutairi A; Department of Pathology and Laboratory Medicine, Ministry of National Guard Hospital and Health Affairs (MNGHA), P.O.box 22490, Kingdom of Saudi Arabia. almuitiriab@mngha.med.sa.
  • Alhassoun MI; Department of Pathology and Laboratory Medicine, Ministry of National Guard Hospital and Health Affairs (MNGHA), P.O.box 22490, Kingdom of Saudi Arabia. hassounma@mngha.med.sa.
  • Alniwaider RA; Toxicology Laboratory Department of Pathology and Laboratory Medicine, Ministry of National Guard Hospital and Health Affairs (MNGHA), P.O. box 22490, Kingdom of Saudi Arabia. alniwaiderra@ngha.med.sa.
  • Habib AH; Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. ahabib@kau.edu.sa.
  • Sain ZM; Department of Microbiology, Faculty of Medicine, Rabigh. King Abdulaziz University. Jeddah, 21589, KSA. zsain@kau.edu.sa.
  • Misbahuddin M Rafeeq; Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, Saudi Arabia. misbahuddinrafeeq@yahoo.com.
Cell Mol Biol (Noisy-le-grand) ; 70(8): 64-75, 2024 Sep 08.
Article em En | MEDLINE | ID: mdl-39262261
ABSTRACT
Alzheimer's disease (AD) is a significant global healthcare challenge, particularly in the elderly population. This neurodegenerative disorder is characterized by impaired memory and progressive decline in cognitive function. BACE1, a transmembrane protein found in neurons, oligodendrocytes, and astrocytes, exhibits varying levels across different neural subtypes. Abnormal BACE1 activity in the brains of individuals with AD leads to the formation of beta-amyloid proteins. The complex interplay between myelin sheath formation, BACE1 activity, and beta-amyloid accumulation suggests a critical role in understanding the pathological mechanisms of AD. The primary objective of this study was to identify molecular inhibitors that target Aß. Structure-based virtual screening (SBVS) was employed using the MCULE database, which houses over 2 million chemical compounds. A total of 59 molecules were selected after the toxicity profiling. Subsequently, five compounds conforming to the Egan-Egg permeation predictive model of the ADME rules were selected and subjected to molecular docking using AutoDock Vina on the Mcule drug discovery platform. The top two ligands and the positive control, 5HA, were subjected to molecular dynamics simulation for five nanoseconds. Toxicity profiling, physiochemical properties, lipophilicity, solubility, pharmacokinetics, druglikeness, medicinal chemistry attributes, average potential energy, RMSD, RMSF, and Rg analyses were conducted to identify the ligand MCULE-9199128437-0-2 as a promising inhibitor of BACE1.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ácido Aspártico Endopeptidases / Secretases da Proteína Precursora do Amiloide / Simulação de Dinâmica Molecular / Doença de Alzheimer / Simulação de Acoplamento Molecular Limite: Humans Idioma: En Revista: Cell Mol Biol (Noisy-le-grand) Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Arábia Saudita País de publicação: França
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ácido Aspártico Endopeptidases / Secretases da Proteína Precursora do Amiloide / Simulação de Dinâmica Molecular / Doença de Alzheimer / Simulação de Acoplamento Molecular Limite: Humans Idioma: En Revista: Cell Mol Biol (Noisy-le-grand) Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Arábia Saudita País de publicação: França