IN SILICO EVALUATION OF CSF1R INHIBITORS: A PROMISING APPROACH FOR TARGETING NEUROINFLAMMATION IN NEURODEGENERATIVE DISEASES

Abstract

Objective: This study investigates the therapeutic potential of Colony Stimulating Factor 1 Receptor (CSF1R) inhibitors in targeting neuroinflammation, focusing on the modulation of the JNK/NLRP3/IL-1β signaling pathway, a key axis contributing to neurodegenerative and neuropsychiatric diseases.

Methods: In silico docking analyses were conducted to evaluate the interactions between CSF1R inhibitors and pivotal inflammatory proteins (JNK, NLRP3, IL-1β). Molecular Dynamics (MD) simulations assessed the stability and conformational dynamics of the ligand-protein complexes. The inhibitors' physicochemical and ADME profiles and toxicity characteristics were analyzed using QikProp and computational toxicity prediction tools.

Results: The docking studies demonstrated that BLZ945 exhibits superior binding affinities with docking scores of-11.107 kcal/mol for JNK, -9.870 kcal/mol for NLRP3, and -4.872 kcal/mol for IL-1β, surpassing other inhibitors such as chiauranib and pexidartinib. ADME analysis revealed that BLZ945 has favorable drug-like properties, including high oral bioavailability (94.025%) and effective blood-brain barrier penetration (QPlogBB:-1.159). Toxicity evaluations confirmed its low toxicity profile, positioning it as a safer candidate compared to edicotinib and ARRY382. MD simulations further validated the stability of BLZ945 in complex with JNK and NLRP3, showing minimal root mean square deviation (RMSD: 2.38–3.55 Å) and strong hydrophobic interactions with key residues.

Conclusion: The findings highlight BLZ945 as a promising CSF1R inhibitor for modulating the JNK/NLRP3/IL-1β pathway, offering potential therapeutic benefits for neuroinflammation-related disorders. Its high binding affinities, favorable ADME properties, and stable interactions in MD simulations underscore its suitability for further experimental validation in neurodegenerative disease models.