In Silico Assessment of Drug-Like Properties of Phytocannabinoids in Cannabis Sativa
This study investigated drug-like properties of phytocannabinoids in Cannabis sativa using an in silico study. We report sixteen phytocannabinoids: cannabidiol (CBD), cannabidiolic acid (CBDA), cannabinol (CBN), cannabichromene (CBC), cannabigerol (CBG), cannabicyclol (CBL), cannabivarin (CBV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabinodiol (CBDL), cannabielsoin (CBE), cannabitriol (CBT), Δ9-tetrahydrocannabinol (Δ9-THC), Δ9-tetrahydrocannabivarin (Δ9-THCV), and Δ8-tetrahydrocannabinol (Δ8-THC). All chemical structures and properties were obtained from PubChem Compound, National Center for Biotechnology Information,U.S. National Library of Medicine. Molinspiration was used for the calculation of molecular properties and bioactivity score. The parameters were molecular weight (MW), number of hydrogen acceptor (HBA), number of hydrogen donor (HBD), partition coefficient (cLogP), polar surface area (PSA) and number of rotatable bonds (NROTB). We predicted bioactivity scores for G Protein-Coupled Receptors (GPCR) ligand, ion channel modulator, kinase inhibitor, nuclear receptor ligand, protease inhibitor and enzyme inhibitor. Lipinski’s rule was used as reference to determine the drug-like properties of the phytocannabinoids. All compounds have MW<500, HBA<10, HBD<5, TPSA<140Å2 and NRTOB<10. Bioactivity score showed an active or moderately active in all compounds. Fifteen compounds were detected to have one violation. CBT did not violate any of the Lipinski’s Ro5 and demonstrated as a good drug-like property and for oral absorption. This suggests that CBT can be further tested for potential orally active drugs.
in Phytocannabinoids: Unravelling the complex chemistry and pharmacology of Cannabis sativa. Springer
International Publishing Switzerland, 1-36.
Burstein, S. (2015). Cannabidiol (CBD) and its analogs: a review of their effects on inflammation. Bioorgan.
Med. Chem. 23, 1377–1385.
Andre, C.M., Hausman, J. and Guerriero, G. (2016). Cannabis sativa: The plant of the thousand and one molecules. Frontier in Plant Science. 7(19).
Giacoppo, S., Mandolino, G., Galuppo, M., Bramanti, P. and Mazzon, E. (2014). Cannabinoids: new promising
agents in the treatment of neurological diseases. Molecules. 19, 18781–18816.
Javid F.A., Phillips, R.M., Afshinjavid, S., Verde, R and Ligresti, A. (2016). Cannabinoid pharmacology in cancer research: A new hope for cancer patients? European Journal of Pharmacology, 775, 1-14
DeLong, G. T., Wolf, C. E., Poklis, A., and Lichtman, A. H. (2010). Pharmacological evaluation of the natural
constituent of Cannabis sativa, Cannabichromene and its modulation by tetrahydrocannabinol. Drug Alcohol
Isahq M.S., Afridi, M.S., Ali, J., Hussain, M.M., Ahmad, S. and Kanwal, S. (2015). Proximate composition,
phytochemical screening, GC-MS studies of biologically active cannabinoids and antimicrobial activities of
Cannabis indica. Asian Pacific Journal of Tropical Disease. 5 (11), 897-902.
Rajan,T.S., Giacoppo,S.,Iori, R., De Nicola, G.S., Grassi, G., Pollastro, F., Bramanti, P. and Mazzon, E. (2016).
Anti-inflammatory and antioxidant effects of a combination of cannabidiol and moringin in LPS-stimulated
macrophages. Fitoterapia. 112,104-115.
Gould, J. (2015). The Cannabis crop. Nature. 525, S2–S3.
Lipinski, C.A. (1997). Experimental and computational approaches to estimate solubility and permeability in
drug discovery and development settings. Adv. Drug Deliv. Rev. 23, 3-25.
Abraham, M.H., Chada, H.S., Mitchell, R.C.(1994). Hydrogen bonding. 33 factors that influence the distribution
of solutes between blood and brain. J. Pharm. Sci. 83,1257–1268.
Krämer, S.D., Aschmann, H.E., Hatibovic,M., Hermann, K.F., Neuhaus, C.S., Brunner, C., Belli, S. (2016). When
barriers ignore the “rule-of-five”. Adv. Drug Deliv. Rev. 62-74.
Prasanna, S., Doerrksen, R.J. (2009). Topological polar surface area: A useful descriptor in 2D-QSAR. Curr Med
[Yu, C., Zhang X.D., Guan, H.Y., Gr, C.H., Wu, Y., Han, G.X. (2007). Prediction of solvation for energy of small
organic moleculars based on support vector regression algorithm. Chemistrymag 9:54.
Macarron, R., Leungo, J.I., (2011). Yin and Yang in medicinal chemistry: what does drug-likeness mean? Future
Lipinski, C.A., Lombardo, F., Dominy, B.W., Feeney, P.J. (2001). Experimental and computational approaches
to estimate solubility and permeability in drug discovery and development settings. Adv Drug Rev. 46:3-26
Benet, L.Z., Hosey, C.M., Ursu, O., Oprea, T.I. (2016). BDDCS, the Rule of 5 and drugability. Adv Drug Rev.101:89-98.
Wu, C.Y., Benet, L.Z. (2005). Predicting drug disposition via application of BCS:transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm. Res. 22:11-23.
Lipinski, A. C. (2016). Rule of five in 2015 and beyond: Target ad ligand structural limitations, ligand chemistry
structure and drug discovery project decisions. Adv Drug Rev. 101: 34-41
Desa, S., Schwabe, A.,.McGlaughlin, M, Brown, C.E., Hyslop, R.M. (2017). Analysis of chemotypes in retail Cannabis strains. 253rd American Chemical Society National Meeting & Exposition, San Francisco, CA. 2-6 April, 2017.
Hyslop, R.M., Saviola, A., Bydalek, S., Brown, C.E., Desa, S., Thomas, M., Magiotta, A, Mackessy, S., Hansen,
C., Brown, M. (2017). In vitro anti-neoplastic activity of specific phytocannabinoids of Cannabis sativa. 253rd
American Chemical Society National Meeting & Exposition, San Francisco, CA. 2-6 April, 2017.
Hyslop, R.M., Brown, C.E., Magiotta A., Morgan, B., Brown, M., Sherman, T., Petty, D., Desa, S., O’Neil, J.,
Flora, S., Kellogg, K., Hansen, C., Bydalek, S., Cale, T., Laster, C., Folsom, J., Hawkinson, A. (2017).
Development of a cannabinoid-based Cell-in-a Box® therapeutic system targeted toward malignant tumors.
253rd American Chemical Society National Meeting & Exposition, San Francisco, CA. 2-6 April, 2017.
Tian, S., Wang, J., Li, Y., Li, D., Xu, L., Hou, T. (2015). The application of in silico drug-likeness predictions in
pharmaceutical research. Adv Drug Delivery Reviews. 86: 2-10
Obata, Y., Ishikawa, Y. (1966). Studies on the Constituents of Hemp Plant (Cannabis sativa L.) Agricultural and
Biological Chemistry. 30(6), 619-620
McPhail, A.T., ElSohly, H.N., Turner, C.E., ElSohly, M.A. (1984). Stereochemical assignments for the two enantiomeric pairs of 9,10-dihydroxy-Δ6a (10a) tetrahydrocannabinols x-ray crystal structure analysis of (±)
trans-cannabitriol. J. Nat. Prod. 47(1):138–142
National Center for Biotechnology Information. PubChem Compound Database; CID=11551959,
https://pubchem.ncbi.nlm.nih.gov/compound/11551959 (accessed Oct. 1, 2017).
El- Kattan, A., Varma, M. (2012). Oral Absorption, Intestinal Metabolism and Human Oral Bioavailability,
Topics on Drug Metabolism, Dr. James Paxton (Ed.), InTech, DOI: 10.5772/31087. Available from: