Phospholipid-Based Prodrugs for Drug Targeting in Inflammatory Bowel Disease: Computational Optimization and In-Vitro Correlation

Author(s): Arik Dahan , Shimon Ben-Shabat , Noa Cohen , Shahar Keinan , Igor Kurnikov , Aaron Aponick , Ellen M. Zimmermann .

Journal Name: Current Topics in Medicinal Chemistry

Volume 16 , Issue 23 , 2016

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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.

Keywords: Drug targeting, Inflammatory bowel disease (IBD), Molecular Dynamics, Phospholipase A2 (PLA2), Prodrugactivating enzyme, Thermodynamic integration, Umbrella Sampling/WHAM methods.

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Article Details

Year: 2016
Page: [2543 - 2548]
Pages: 6
DOI: 10.2174/1568026616666160414122913
Price: $58

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