Discerning potent CSF-1r inhibitors for targeting and therapy of neuroinflammation using computational approaches
Anupriya Adhikari1, Anwesh Pandey2
1Department of Chemistry, Graphic Era Hill University, Dehradun, India.
Abstract:
Microglia, the primary cellular mediator of neuroinflammation, plays a pivotal role in numerous neurological disorders. Precise and non-invasive quantification of microglia is of paramount importance. Despite various investigations into cell-specific biomarkers for assessing neuroinflammation, many suffer from poor cellular specificity and low signal-to-noise ratios. Colony-stimulating factor-1 receptor (CSF-1R), also known as FMS kinase, has emerged as a promising neuroinflammation biomarker with significant relevance to inflammatory diseases. Additionally, CSF-1R inhibitors (CSF-1Ri) have shown therapeutic potential in central nervous system (CNS) pathological conditions by depleting microglia. Therefore, the development of more specific CSF-1R inhibitors for targeting and treating various CNS insults and neurological disorders is imperative. This study focuses on the search for novel CSF-1R inhibitors. Based on the literature on CSF-1R inhibitors, we proposed and investigated ten ligands as novel CSF-1R inhibitors. Among these, the top three ligands, selected based on their maximum binding scores in docking calculations, are subjected to 100 nanoseconds of molecular dynamics (MD) simulation, alongside three reference ligands. All protein-ligand complexes remain stable throughout the dynamics and exhibit minimal fluctuations during the analysis. The results obtained through this study may prove significant for the future design of CSF-1R inhibitors with potential applications in the field of biomedicine.
Insights
Researchers identified novel ligands targeting Colony-stimulating factor-1 receptor (CSF-1R) to combat neuroinflammation. These potential CSF-1R inhibitors show promise for treating neurological disorders by modulating microglia activity.
Area of Science:
- Neuroscience
- Pharmacology
- Computational Chemistry
Background:
- Microglia are key mediators of neuroinflammation, implicated in various neurological disorders.
- Accurate, non-invasive quantification of microglia is crucial for understanding and treating these conditions.
- Existing neuroinflammation biomarkers often lack specificity and have low signal-to-noise ratios.
Purpose of the Study:
- To identify novel inhibitors targeting Colony-stimulating factor-1 receptor (CSF-1R), a promising biomarker for neuroinflammation.
- To explore the therapeutic potential of CSF-1R inhibitors in central nervous system (CNS) disorders.
- To develop more specific CSF-1R inhibitors for treating CNS insults and neurological diseases.
Main Methods:
- Literature review to identify potential CSF-1R inhibitors.
- In silico screening and docking calculations to evaluate ten proposed ligands.
- Molecular dynamics (MD) simulations of the top three ligands and three reference ligands complexed with CSF-1R.
Main Results:
- Ten novel ligands were proposed and investigated as potential CSF-1R inhibitors.
- Top three ligands demonstrated significant binding scores in docking studies.
- MD simulations confirmed the stability of protein-ligand complexes, with minimal fluctuations observed.
Conclusions:
- The study successfully identified promising novel ligands for CSF-1R inhibition.
- These findings provide a foundation for the future design of targeted CSF-1R inhibitors.
- The developed inhibitors hold potential for therapeutic applications in neuroinflammatory diseases and CNS disorders.
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