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Virtual screening and molecular dynamics simulation approach for the identification of potential multi-target directed ligands for the treatment of Alzheimer's disease.
Jangid, Kailash; Devi, Bharti; Sahoo, Ashrulochan; Kumar, Vijay; Dwivedi, Ashish Ranjan; Thareja, Suresh; Kumar, Rajnish; Kumar, Vinod.
Afiliación
  • Jangid K; Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Central University of Punjab, Bathinda, Punjab, India.
  • Devi B; Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, Punjab, India.
  • Sahoo A; Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, BHU, Varanasi, Uttar Pradesh, India.
  • Kumar V; Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, Punjab, India.
  • Dwivedi AR; Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Central University of Punjab, Bathinda, Punjab, India.
  • Thareja S; Department of Medicinal Chemistry, Gitam School of Pharmacy Hyderabad, Hyderabad, Telangana, India.
  • Kumar R; Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, Punjab, India.
  • Kumar V; Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, BHU, Varanasi, Uttar Pradesh, India.
J Biomol Struct Dyn ; 42(1): 509-527, 2024.
Article en En | MEDLINE | ID: mdl-37114423
Alzheimer's disease (AD) is a multifactorial neurological disorder characterized by memory loss and cognitive impairment. The currently available single-targeting drugs have miserably failed in the treatment of AD, and multi-target directed ligands (MTDLs) are being explored as an alternative treatment strategy. Cholinesterase and monoamine oxidase enzymes are reported to play a crucial role in the pathology of AD, and multipotent ligands targeting these two enzymes simultaneously are under various phases of design and development. Recent studies have revealed that computational approaches are robust and trusted tools for identifying novel therapeutics. The current research work is focused on the development of potential multi-target directed ligands that simultaneously inhibit acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) enzymes employing a structure-based virtual screening (SBVS) approach. The ASINEX database was screened after applying pan assay interference and drug-likeness filter to identify novel molecules using three docking precision criteria; High Throughput Virtual Screening (HTVS), Standard Precision (SP), and Extra Precision (XP). Additionally, binding free energy calculations, ADME, and molecular dynamic simulations were employed to get structural insights into the mechanism of protein-ligand binding and pharmacokinetic properties. Three lead molecules viz. AOP19078710, BAS00314308 and BDD26909696 were successfully identified with binding scores of -10.565, -10.543 & -8.066 kcal/mol against AChE and -11.019, -12.357 & -10.068 kcal/mol against MAO-B, better score as compared to the standard inhibitors. In the near future, these molecules will be synthesized and evaluated through in vitro and in vivo assays for their inhibition potential against AChE and MAO-B enzymes.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Simulación de Dinámica Molecular / Enfermedad de Alzheimer Tipo de estudio: Diagnostic_studies / Prognostic_studies / Screening_studies Límite: Humans Idioma: En Revista: J Biomol Struct Dyn Año: 2024 Tipo del documento: Article País de afiliación: India Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Simulación de Dinámica Molecular / Enfermedad de Alzheimer Tipo de estudio: Diagnostic_studies / Prognostic_studies / Screening_studies Límite: Humans Idioma: En Revista: J Biomol Struct Dyn Año: 2024 Tipo del documento: Article País de afiliación: India Pais de publicación: Reino Unido