Discerning potent CSF-1r inhibitors for targeting and therapy of neuroinflammation using computational approaches

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.