Journal
CURRENT TOPICS IN MEDICINAL CHEMISTRY
Volume 16, Issue 23, Pages 2543-2548Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1568026616666160414122913
Keywords
Drug targeting; Inflammatory bowel disease (IBD); Molecular Dynamics; Phospholipase A(2) (PLA(2)); Prodrug-activating enzyme; Thermodynamic integration; Umbrella Sampling/WHAM methods
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Funding
- University of Florida Gatorade Trust
- US-Israel Binational Science Foundation (BSF)
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In inflammatory bowel disease (IBD) patients, the enzyme phospholipase A(2) (PLA(2)) 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 PLA(2) with both human and bee venom PLA(2). 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.
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