Study on indole CB2 ligands based on 3D-QSAR, molecular docking and molecular dynamics simulation

Cannabinoid receptor type 2 (CB2) is a very promising therapeutic target for a variety of potential indications, such as cancer, inflammation, immune regulation and so on. However, no CB2-targeting drug has been approved to date. Therefore, it would be beneficial to explore new CB2 ligands. A 3D-QSAR study for CB2 receptor ligands were developed based on CoMFA and CoMSIA models, using 21 CB2 agonists previously reported by our laboratory. The results indicate that both CoMFA (N = 4, q² = 0.645, r² = 0.984) and CoMSIA (N = 6, q² = 0.516, r² = 0.970) have good predictive ability and stability. Contour maps of the CoMFA and CoMSIA models provide the relationship between steric effects, electrostatic effects, etc. and enhanced CB2 ligand activity. This information was used to design 1240 structurally novel compounds. The activity prediction, pharmacophore screening, molecular docking and ADME/T prediction of the designed molecules were performed in turn, and the final compound AL18 was hit. AL18 was evaluated for stability studies by molecular dynamics simulation studies. AL18 showed better stability than reference standards (GW405833, compound 2) in studied parameters such as RMSD, RMSF, Rg, etc. The binding free energy based on MM/PBSA of AL18 is −35.191 kcal mol⁻¹, indicating strong binding interactions. AL18 can be explored as a lead compound for early research, which has not yet been experimentally explored. This study also provides a strong theoretical foundation for the subsequent design and development of indole CB2 ligands.