Phospholipid-based prodrugs for drug targeting in inflammatory bowel disease: Computational optimization and in-vitro correlation

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 drug development.