Molecular Modeling of the Major Compounds of Sesquiterpenes Class in Copaiba Oil-resin

Aims: To study the Structure-Activity Relationship (SAR) and pharmacokinetic and toxicological properties (ADME/Tox) of the major compounds of sesquiterpenes class oil-resin extracted from the copaiba, using quantum chemistry methods B3LYP/6-31G*, employing the resulting information as a guide to obtain more stable compounds, less reactive and toxic with better absorption, distribution, metabolism and excretion.
Place and Duration of Study: Laboratory of Modeling and Computational Chemistry (LMCC) at Federal University of Amapá (UNIFAP), Macapá, Brazil, between March 2014 and February 2015.
Methodology: Major compounds were selected from the literature, totaling 12 compounds, and modeled with the GaussView 5.0 program. The optimization was performed using the DFT method and B3LYP/6-31G* base set implemented in the Gaussian 03 program. Maps of molecular electrostatic potential (MEP's) were generated from the atomic charges, and the construction of the MEP's and frontier orbital’s (HOMO and LUMO) were visualized with the aid of Molekel program. Pharmacophore pattern was determined from the online server PharmaGist, and the ADME/Tox properties of the compounds studied were calculated using the online server PreADMET and the results were compared with those of DEREK software.
Results: MEP's in the compounds studied have shown no uniformity in their region of electrostatic potential. HOMO is localized to at the double bonds (C=C), and LUMO orbitals were on the carbon atoms of the double bonds. Pharmacophore pattern evidenced 11 regions hydrophobic. Pharmacokinetic property of human intestinal absorption (HIA) was 100% for all compounds. Cell permeability PCaCO2 was classified as medium, and the values ranged from 56.3475 nm/sec (compound 2) to 23.405 nm/sec (compound 10). Cell permeability PMDCK was classified as high, because presented higher values than 25 nm/sec, ranging from 218.885 nm/sec (compound 2) to 40.0711 nm/sec (compounds 7 and 11). The compounds showed strong plasma protein binding with values ranging from 90.849656% (compound 2) to 100% for the other compounds. Penetration of the blood brain barrier was classified as active (CBrain/CBlood>1), and the values ranged from 3.75249 (compound 2) to 15.0642 (compound 10). Therefore, these compounds studied evidenced toxic effects on the CNS. In toxicity tests, the compounds 1-2, 4-6 and 8-10 show mutagenic predictions, and only the compounds 3, 7, 11 and 12 presented non-mutagenic predictions. Carcinogenicity was significant in mouse. However, the predictions in rats the compounds 1-4 and 6-12 presented positive predictions (non-carcinogenic), and only the compound 5 showed a negative prediction (evidence of carcinogenicity), when analyzed in DEREK software the compounds showed no toxiphoric alerts generated by epoxides groups.
Conclusion: The B3LYP/6-31G* method was adequate to optimize the major compounds of copaiba oil-resin. Compounds studied are viable for administration in different pathways, and may have their improved pharmacokinetic properties according to the formulation to enhance the efficacy and safety.