In inflammatory bowel disease (IBD) patients, the enzyme phospholipase
A2 (PLA2) is overexpressed in the inflamed intestinal tissue, and hence may be exploited
as a prodrug-activating enzyme allowing drug targeting to the site(s) of gut
inflammation. The purpose of this work was to develop powerful modern computational
approaches, to allow optimized a-priori design of phospholipid (PL) based prodrugs for IBD drug targeting. We
performed simulations that predict the activation of PL-drug conjugates by PLA2 with both human and bee venom PLA2.
The calculated results correlated well with in-vitro experimental data. In conclusion, a-priori drug design using a computational
approach complements and extends experimentally derived data, and may improve resource utilization and speed
Keywords: Drug targeting, Inflammatory bowel disease (IBD), Molecular Dynamics, Phospholipase A2 (PLA2), Prodrugactivating
enzyme, Thermodynamic integration, Umbrella Sampling/WHAM methods.
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