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

ATHIRA SASIDHARAN; DEEPTHI K.; SHESHAGIRI DIXIT; DEEPSHIKHA SINGH; VEENA V. TOM; YOGISH SOMAYAJI; RONALD FERNANDES

doi:10.22159/ijap.2025v17i2.53425

Authors

ATHIRA SASIDHARAN Department of Allied Health Sciences, NGSM Institute of Pharmaceutical Sciences, Nitte (Deemed to be University), Mangalore-575018, Karnataka, India https://orcid.org/0009-0000-9886-2124
DEEPTHI K. Department of Pharmaceutical Chemistry, NGSM Institute of Pharmaceutical Sciences, Nitte (Deemed to be University), Mangalore-575018, Karnataka, India https://orcid.org/0000-0001-7046-2938
SHESHAGIRI DIXIT Computer Aided Drug Design Laboratory, Department of Pharmaceutical Chemistry, JSS College of Pharmacy Mysore, JSS Academy of Higher Education and Research, Mysore-570015, Karnataka, India. https://orcid.org/0000-0003-3966-7278
DEEPSHIKHA SINGH Department of Pharmaceutical Chemistry, JSS College of Pharmacy Mysore, JSS Academy of Higher Education and Research, Mysore-570015, Karnataka, India https://orcid.org/0000-0003-4030-5610
VEENA V. TOM Department of Allied Health Sciences, NGSM Institute of Pharmaceutical Sciences, Nitte (Deemed to be University), Mangalore-575018, Karnataka, India https://orcid.org/0009-0001-6856-3323
YOGISH SOMAYAJI Department of Post Graduate Studies and Research in Biochemistry, St. Aloysius College (Autonomous), Mangaluru -575003, Karnataka, India https://orcid.org/0000-0002-8946-1633
RONALD FERNANDES Department of Pharmaceutical Chemistry, NGSM Institute of Pharmaceutical Sciences, Nitte (Deemed to be University), Mangalore-575018, Karnataka, India

DOI:

https://doi.org/10.22159/ijap.2025v17i2.53425

Keywords:

CSF1R inhibitors, Neuroinflammation, JNK/NLRP3/IL-1β pathway, In silico docking, Molecular dynamics (MD) simulations, ADME characteristics

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.

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