Frontiers in Drug Discovery · Published 2026-05-15 · DOI 10.3389/fddsv.2026.1809420
Fernanda F. De Souza, Juliana F. Vilachã, Heberth De Paula, Kathia Maria Honorio
Osteoarthritis is a chronic, degenerative joint disease characterized by cartilage breakdown, inflammation, and pain, significantly affecting the quality of life of affected individuals. 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 (PubChem CID: 154468691, 4-[[(1R,2S,6S,14R,15R,16R)-11,15-dimethoxy-5-methyl-13-oxahexacyclo [13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-16-yl]methoxymethyl]-3,5-dimethyl-1,2-oxazole) for further evaluation, using WIN55,212-2 (PubChem CID: 5311501, [(11R)-2-methyl-11-(morpholin-4-ylmethyl)-9-oxa-1-azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-3-yl]-naphthalen-1-ylmethanone) as a reference agonist. Molecular dynamics simulations (500 ns) were also conducted in triplicate 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 with an average RMSD of 0.4 nm. Analysis of the most stable replicates through MM/PBSA binding free energy calculations yielded −51.00 kcal/mol for CB2R-P415 and -55.65 kcal/mol for CB2R-WIN55,212-2. ADMET predictions indicated that P415 possesses drug-like properties, including a log P of 3.36, TPSA of 62.95 Å2, and an LD50 of 3.086 mg/kg, with no predicted AMES toxicity or hepatotoxicity. 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.
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Souza, F., Vilachã, J., Paula, H., et al. (2026). Virtual screening and molecular dynamics simulations of cannabinoid receptor 2 agonists as drug candidates for osteoarthritis therapy. Frontiers in Drug Discovery. https://doi.org/10.3389/fddsv.2026.1809420