Pharmacophore Elucidation and Molecular Docking Studies on 5-Phenyl-1-(3-pyridyl)-1H-124-triazole-3-carboxylic Acid Derivatives as COX-2 Inhibitors

摘要

A set of 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid derivatives (>16–32) showing anti-inflammatory activity was analyzed using a three-dimensional qualitative structure-selectivity relationship (3D QSSR) method. The CatalystHipHop approach was used to generate a pharmacophore model for cyclooxygenase-2 (COX-2) inhibitors based on a training set of 15 active inhibitors (>1–15). The degree of fitting of the test set compounds (>16–32) to the generated hypothetical model revealed a qualitative measure of the more or less selective COX-2 inhibition of these compounds. The results indicate that most derivatives (>16, >18, >20–25, and >30–32) are able to effectively satisfy the proposed pharmacophore geometry using energy accessible conformers (Econf < 20 kcal/mol). In addition, the triazole derivatives (>16–32) were docked into COX-1 and COX-2 X-ray structures, using the program GOLD. Based on the docking results it is suggested that several of these novel triazole derivatives are active COX inhibitors with a significant preference for COX-2. In principle, this work presents an interesting, comprehensive approach to theoretically predict the mode of action of compounds that showed anti-inflammatory activity in an in vivo model.