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In Silico Identification of Multi-Target Ligands as Promising Hit Compounds for Neurodegenerative Diseases Drug Development.
Alov, Petko; Stoimenov, Hristo; Lessigiarska, Iglika; Pencheva, Tania; Tzvetkov, Nikolay T; Pajeva, Ilza; Tsakovska, Ivanka.
Afiliación
  • Alov P; Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 105, 1113 Sofia, Bulgaria.
  • Stoimenov H; Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 105, 1113 Sofia, Bulgaria.
  • Lessigiarska I; Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 105, 1113 Sofia, Bulgaria.
  • Pencheva T; Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 105, 1113 Sofia, Bulgaria.
  • Tzvetkov NT; Institute of Molecular Biology "Acad. Roumen Tsanev", Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 21, 1113 Sofia, Bulgaria.
  • Pajeva I; Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 105, 1113 Sofia, Bulgaria.
  • Tsakovska I; Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 105, 1113 Sofia, Bulgaria.
Int J Mol Sci ; 23(21)2022 Nov 07.
Article en En | MEDLINE | ID: mdl-36362434
The conventional treatment of neurodegenerative diseases (NDDs) is based on the "one molecule-one target" paradigm. To combat the multifactorial nature of NDDs, the focus is now shifted toward the development of small-molecule-based compounds that can modulate more than one protein target, known as "multi-target-directed ligands" (MTDLs), while having low affinity for proteins that are irrelevant for the therapy. The in silico approaches have demonstrated a potential to be a suitable tool for the identification of MTDLs as promising drug candidates with reduction in cost and time for research and development. In this study more than 650,000 compounds were screened by a series of in silico approaches to identify drug-like compounds with predicted activity simultaneously towards three important proteins in the NDDs symptomatic treatment: acetylcholinesterase (AChE), histone deacetylase 2 (HDAC2), and monoamine oxidase B (MAO-B). The compounds with affinities below 5.0 µM for all studied targets were additionally filtered to remove known non-specifically binding or unstable compounds. The selected four hits underwent subsequent refinement through in silico blood-brain barrier penetration estimation, safety evaluation, and molecular dynamics simulations resulting in two hit compounds that constitute a rational basis for further development of multi-target active compounds against NDDs.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Acetilcolinesterasa / Enfermedades Neurodegenerativas Tipo de estudio: Diagnostic_studies Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2022 Tipo del documento: Article País de afiliación: Bulgaria Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Acetilcolinesterasa / Enfermedades Neurodegenerativas Tipo de estudio: Diagnostic_studies Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2022 Tipo del documento: Article País de afiliación: Bulgaria Pais de publicación: Suiza