ANTI-INFLAMMATORY PROPERTIES OF SPIROCYCLES FROM Villorita cyprinoides: A CHEMOINFORMATIC APPROACH
Corbiculid black clam Villorita cyprinoides is traditional seafood among the coastal populace of southwest coast of India. These were reported for bioactive functionalities with respect to anti-inflammatory properties. Biochemical investigation of V. cyprinoides resulted in the characterization of two O-spirocyclic derivatives (1-2). The structures were elucidated through comprehensive spectroscopic methods (Fourier transform infrared, mass and nuclear magnetic resonance experiments). In vitro inhibitory properties of the O-spirocyclic analogues determined their anti-inflammatory potentials. These specialized metabolites were demonstrated potent anti-inflammatory activities against cyclooxygenase-2 (COX-2 IC50 < 0.75 mg/mL) and 5-lipoxygenase (5-LOX IC50 0.75-0.80 mg/mL) enzymes. Molecular docking simulations described the effective interactions of the spirocyclic compounds in the COX-2 and 5-LOX inflammation models. The spirocyclic derivative, 2 registered lowest binding energy and docking score of -8.98 and -10.85 kcal/mol, respectively compared to those exhibited by 1 (-8.72 and -10.26 kcal/mol, respectively) against COX-2 enzyme. Similarly, spirocyclic derivative, 2 registered lesser binding energy (-7.58 kcal/mol) and docking score (-9.20 kcal/mol) against 5-LOX followed by 1 (-5.06 and -8.54 kcal/mol, respectively). The lowest binding energy/docking score along with greater number of hydrogen bonding interactions in the active sites of COX-2 and 5-LOX manifested towards the greater anti-inflammatory properties of spirocyclic derivative, 2 compared to 1. Thus, the oxygenated spirocyclic metabolites derived from V. cyprinoides were found to be dual inhibitors of pro-inflammatory COX-2 and 5-LOX enzymes. In particular, the spirocyclic derivative, 2 displayed significantly greater anti-lipoxygenase properties compared to other homologue, and therefore, could be used as potent anti-inflammatory leads in the pharmaceutical preparations.
