• Molecular docking study of lignanamides from Cannabis Sativa against P-glycoprotein
  • Farnoosh kazemi,1,* Isaac Karimi ,2 Namdar Yousofvand,3
    1. Department of Biology, Faculty of Science, Razi University
    2. Department of Biology, Faculty of Science, Razi University
    3. Department of Biology, Faculty of Science, Razi University


  • Introduction: P-glycoprotein (P-gp), which was first identified in cancer cells, is an ATP-dependent efflux transporter that expels a wide variety of cytotoxic compounds out of cells. This transporter can decrease the bioavailability of therapeutic drugs by preventing their sufficient intracellular accumulation. Over expression of P-gp in cancer cells lead to multidrug resistance (MDR) phenotype that is one of the main reasons for the failure of chemotherapy. Hence, P-gp inhibition is a favorable method to reverse MDR. In this study, the lignanamides from Cannabis sativa were docked against P-gp to recognize potential binding affinities of these phytochemicals.
  • Methods: To study the binding modes of ligands in drug-binding pocket of P-gp, the crystal structure of P-gp (PDB ID: 4Q9H) was retrieved from Protein Data Bank (PDB; http://www.RCSB.org). The lignanamides from Cannabis sativa including cannabisin A, B, C, D, E, F, G, M, N and grossamide were used as the ligands. Tariquidar and zosuquidar, two well-known P-gp inhibitors, were selected as the control ligands. To get ready the structures, adding hydrogens and energy minimizing were performed by Molegro Virtual Docker and Chimera 1.13. Docking calculations were done by using Autodock vina in PyRx 0.8 to determine the best pose of each of the ligands (the most negative binding affinity). Finally, LigPlot+ was used to analyze protein-ligand complexes based on the type of interactions (bonding and nonbonding). In addition, to analyze absorption, distribution, metabolism and excretion (ADME) properties, the canonical SMIlES of the ligands were submitted to swissADME.
  • Results: Our study demonstrates that the lignanamids interacted with important residues in drug-binding pocket of P-gp with acceptable binding affinity ranging from -8.9 to -10.2 kcal/mol. Among the ligands best binding affinities were related to cannabisin N and cannabisin M that both have been docked with P-gp with most negative binding affinity (-10.2 kcal/mol) compared to tariquidar and zosuquidar (binding affinity: -10.1 and -9.6 kcal/mol respectively). Based on ADME properties, grossamide, cannabisin F and cannabisin N obeyed ‘Rule of 5’ with 1 violation (MW>500) and consecuently are druglikeness.
  • Conclusion: These data suggest that cannabisin M and cannabisin N could be good drug candidates against P-gp. But more studies are needed in order to prove these results.
  • Keywords: P-glycoprotein, ABC transporter, Cannabis, Lignanamide, Molecular docking