Abstract
Secreted phospholipase A2 (PLA2) plays a critical role in mobilizing arachidonic acid in phospholipids. We have previously reported that PLA2 is inhibited by B-type proanthocyanidins (PaCs). To further understand the inhibitory activity of these compounds, we compared the inhibitory potency of B-type PaCs to that of A-type PaCs and modeled them with PLA2 using in silico techniques. The B-type trimer and tetramer inhibited PLA2 (IC50 = 16 and 10 μM). The A-type compounds were less potent (18-35% inhibition at 50 μM). The active site of PLA2 lies in a hydrophobic tunnel. Modeling studies revealed that the B-type PaCs occupy this tunnel and are stabilized by a number of van der Waals interactions. The result is reduced substrate access to the active site. The A-type compounds can occupy this tunnel only by shifting the N-terminal loop outward. Our data provide a structural basis to screen additional PaCs for anti-PLA2 activity.
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