Identification of novel inhibitors of microglia-specific proteins responsible for neuroinflammatory response by molecular docking and simulation studies

Microglia plays an essential role in regulating brain-specific immunity. Upregulation of microglia-specific proteins, such as ionized Ca⁺² binding adaptor-1 (IBA1), colony-stimulating factor 1 receptor (CSF1R), cluster of differentiation 40 ligand (CD40L), and purinergic receptor P2Y12 (P2RY12) is central in driving neuroinflammation-mediated neurodegeneration and poses them as potential targets for drug discovery. Few studies have shown seaweed’s anti-inflammatory and neuroprotective effects, indicating their potential in the management of neuroinflammation. However, molecular targets of the seaweed metabolites on microglia remain elusive. Therefore, 1076 seaweed metabolites obtained from the database were screened for their drug potential. They were followed by molecular docking and simulations to identify potential seaweed metabolites capable of inhibiting microglia-specific proteins responsible for neuroinflammation. Results suggest that Stypoldione may regulate motility, phagocytic activity, and microglia activation by interacting with IBA1 and CSF1R kinase domains. Epitaondiol was observed to likely disrupt the CD40/CD40L pathway and control the expression of cytokines and entry of inflammatory cells into the brain by binding with CD40L. Callophycin A potentially attenuates the chemotactic function of microglia by interacting with P2RY12. Our findings suggest that Stypoldione, Epitaondiol, and Callophycin A may be specific drug ligands that potentially interact with microglia-specific proteins and may regulate microglia-mediated brain immunity.