Mechanistic study on the peripheral cannabinoid-1 receptor blockers based on the tricyclic scaffolds

Cannabinoid-1 receptor (CB1R) is one of the promising targets for treating various diseases, various antagonists, agonists and reverse agonists targeting CB1R have been synthesized and investigated for clinical use. In this work, we used molecular docking and molecular dynamics (MD) simulations to explore the interaction between CB1R and six antagonists: BNS807, BNS808 and BNS809 derived from template 1 and BNS815, BNS816, BNS825 derived from template 2. Six initial conformations were selected for the subsequent MD simulations using molecular docking and cluster analysis. The binding free energy analysis shows that in the three systems of BNS807-CB1R, BNS808-CB1R and BNS809-CB1R, the increase of binding affinity is attributed to the nonpolar contributions of residues Val196, Ala120, Phe200, Phe268, Phe380 and Phe381 and large-volume aromatic substituents are favorable for binding, BNS809 with small substituent CH3 could form the hydrogen bond with Gln115. In the three systems based on template 2, Ile105, Ile116 and Phe177 increase the binding affinity of the antagonists to CB1R. Furthermore, the seven-membered and pyrazole ring of BNS816 formed vdW interactions with Phe170, stabilizing the conformation of BNS816-CB1R. These results reveal the interaction patterns of six peripheral antagonists with CB1R, providing theoretical guidance for the design of drug molecules targeting CB1R.