Molecular Modeling of the Additional Inhibitor Site Located in Secretory Phospholipase A₂

Abstract

Phospholipase A(2) belongs to a super family of enzymes that is massively over expressed in a variety of severe inflammatory diseases, which degrades membrane phospholipids. It has also been reported that this activity leads to loss of tissue, organ integrity and function. This enzyme is an important target for anti-inflammatory drugs. Unsaturated aldehyde terpenoids (non-specific inhibitors) are also being reported, however, they are known to irreversibly modify the enzyme and its action through covalent bond formation. Conformational analysis of secretory phospholipase A(2) indicates that the enzyme's known active site (hydrophobic site) is highly flexible. The studies revealed an additional inhibitor interaction site at the interfacial allosteric binding region of the enzyme. This study unequivocally establishes that non-specific inhibitors like aldehyde terpenoids can simultaneously interact with the enzyme at dual active sites and hence they are reported to be very effective for their inhibitory action.