in silico Evaluation of 4-Amino-5-substituted-4H-1,2,4-triazole-3-thiol Derivatives against DNA Gyrase, COX-2 and Cathepsin B

摘要

Biological activities of 1,2,4-triazoles, in particular, anticancer, anti-inflammatory and antimicrobial activities are potentiated by the presence of thiol group and free amino groups. Enticed by this, a series of 1,2,4-triazole derivatives were designed by introducing different substituent groups at 5th position of 4-arnino-4H-l,2,4-triazole-3-thiol ring and their binding affinities were determined by molecular docking studies with the targets associated with bacterial infections, inflammation and cancer (DNA gyrase, cyclooxygenase-II (COX-2) and cathepsin B; PBD IDs: 1KZN, 3LN1 and 1SP4). Results revealed that all the compounds displayed good binding affinity towards the selected targets. The designed compounds showed relatively good affinity for cathepsin B and DNA gyrase enzymes when compared to COX-2. In comparison to aromatic groups, substitution with long aliphatic chains at 5th position significantly improved the binding properties of the compounds towards the targets. 1,2,4-Triazole ring was found to be crucial to form hydrogen bonding interactions with the active site amino acid residues. Stearyl and oleayl substituted derivatives (B6and B7) exhibited superior binding properties and thus disclosing their pharmacological significance. Interestingly none of the compound showed affinity for permeability glycoprotein (P-gp), suggesting that their cellular uptake will be good in cancer cells.