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In Silico Identification of Multi-Target Ligands as Promising Hit Compounds for Neurodegenerative Diseases Drug Development
- Source :
- International Journal of Molecular Sciences; Volume 23; Issue 21; Pages: 13650
- Publication Year :
- 2022
- Publisher :
- MDPI AG, 2022.
-
Abstract
- 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.
- Subjects :
- Organic Chemistry
Neurodegenerative Diseases
General Medicine
Ligands
Catalysis
Computer Science Applications
Molecular Docking Simulation
Inorganic Chemistry
Structure-Activity Relationship
Drug Development
Acetylcholinesterase
Humans
Cholinesterase Inhibitors
Physical and Theoretical Chemistry
neurodegenerative diseases
acetylcholinesterase
histone deacetylase 2
monoamine oxidase B
multi-target-directed ligands
virtual screening
docking
pharmacophore
molecular dynamics
Monoamine Oxidase
Molecular Biology
Spectroscopy
Subjects
Details
- ISSN :
- 14220067
- Volume :
- 23
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....ed302434bd2b99a41eef9d813874c845
- Full Text :
- https://doi.org/10.3390/ijms232113650