Exploring CB2 Agonists: Virtual Screening and Molecular Dynamics for Osteoarthritis Therapy

Osteoarthritis is a chronic, degenerative joint disease characterized by cartilage breakdown, inflammation, and pain, significantly impacting the quality of life of individuals affected. Current treatments focus on symptom relief but do not halt disease progression, highlighting the need for novel therapeutic strategies. Cannabinoid receptor type 2 (CB2R) has emerged as a promising target for this purpose due to its role in inflammation and pain modulation, with minimal psychoactive effects compared to cannabinoid receptor type 1 (CB1R). This study performed a structure-based virtual screening to identify potential CB2R ligands with high affinity and favorable pharmacokinetic properties. Molecular docking studies led to the selection of compound P415 for further evaluation, using WIN55,212-2 as a reference agonist. Molecular dynamics simulations (500 ns) were also conducted to assess the stability and dynamic behavior of CB2R-ligand complexes. The RMSD and RMSF analyses revealed distinct conformational stability patterns, with the CB2R-P415 complex showing a more stabilized profile over time. The binding free energy calculations further supported these findings, with CB2R-WIN55,212-2 and CB2R-P415 exhibiting favorable interaction energies, particularly with P415 at around -51.00 kcal/mol. ADMET predictions indicated that P415 possesses drug-like properties and is within acceptable toxicity limits. These results suggest that P415 is a promising CB2R ligand with high binding affinity and structural stability, warranting further experimental validation for potential therapeutic applications in osteoarthritis treatment.