Inhibition of key enzymes in the inflammatory pathway by hybrid molecules of terpenes and synthetic drugs: in vitro and in silico studies

THEODULOZ, CRISTINA; ALZATE-MORALES, JANS; JIMÉNEZ-ASPEE, FELIPE; ISLA, MARIA INÉS; ALBERTO, MARÍA ROSA; PERTINO, MARIANO WALTER; SCHMEDA-HIRSCHMANN, GUILLERMO

CHEMICAL BIOLOGY & DRUG DESIGN

WILEY-BLACKWELL PUBLISHING, INC

Año: 2018 p. 1 - 20

1747-0277

The aim of this work was to compare the anti-inflammatory activity of compounds prepared from terpenes and the synthetic drugs ibuprofen and naproxen.The anti-inflammatory activity of the hybrid compounds was compared with the activity of the parent compounds. This was accomplished using in vitro inhibition of LOX and COX -2, and in silico docking studies in 15-LOX and COX-2. The synthesized hybrids showed an inhibition of COX-2 and LOX between 9.8 -57.4% and 0.0-97.7%, respectively. None of the hybrids showed an improvement in the inhibitory effect towards these pro-inflammatory enzymes, compared to the parent terpenes and NSAIDs. The docking studies allowed us to predict the potential binding modes of hybrids6- 15 within COX-2 and 15-LOX active sites.The relative affinity of the compounds inside the binding sites could be explained by forming non covalent interactions with most important and known amino acids reported for those enzymes. A goodcorrelation (r2=0.745) between docking energies and inhibition percentages against COX-2 was found. The high inhibition obtained for compound 10 against COX-2 was explained by hydrogen bond interactions at the enzyme binding site. New synthetic possibilities could be obtained from our in silico models, improving the potency of these hybrid compounds.