MOLECULAR MODELING AS A TOOL TO VALIDATE CYCLOOXYGENASE PROPERTIES OF STEROL ANALOGUES FROM Villoritta cyprinoides

The isolation of solvent extract of V. cyprinoides characterized three previously undisclosed specialized abeo-pregnane-type sterol derivative 19 (10→5) abeo-20-methyl-pregn-10-en-3β-yl-hex-(3′E)-enoate (1) along with two cholestenols (22E),(24¹E)-24¹,24²-dihomocholesta-5,22,24¹-trien-3β-ol (2) and (22E)-24¹-homocholesta-5,22-dien-(3β,24¹β)-diol (3). The in vitro anti-inflammatory (anti-cyclooxygenase-2) activities of 1 were considerably higher (IC₅₀ < 1.10 mg/mL) than 2-3 (IC₅₀ > 1.10 mg/mL). Structure-activity relationship studies demonstrated that bioactive potentials of the titled compounds were linearly related to their electronic factors along with optimum hydrophobic factors. In addition, the molecular docking calculations of sterol analogues, 1-3 were performed against pro-inflammatory COX-2, and their RMSD results were evaluated. In silico docking analyses of candidate compounds with COX-2 receptor suggested that the docked ligands were potentially bound to the target site. The compound 1 recorded lowest binding energy of -8.53 kcal/mol followed by the compounds, 2 and 3 (-7.78 to -7.89 kcal/mol). Similarly, compound 1 registered lowest docking score of -9.71 kcal/mol followed by 2 and 3 (-8.79 to -9.04 kcal/mol). The enzyme inhibition constants, Ki was found to be lesser for compound 1 (0.55 μM) followed by those of 2 (1.63 μM) and 3 (1.97 μM). Also, torsional free energies and intermolecular energies were found to be lesser for 1 (1.19 and -9.73 kcal/mol, respectively) followed by those recorded with 2 (0.89 and -8.79 kcal/mol, respectively) and 3 (1.19 and -8.98 kcal/mol, respectively). The lower docking parameters (inhibition constant, binding energy and docking score) recorded for 1 was appeared to be coherent with its potent in vitro anti-COX-2 assay (IC₅₀ 1.05 mg/mL).