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

[ Vol. 16 , Issue. 23 ]

Author(s):

Arik Dahan, Shimon Ben-Shabat, Noa Cohen, Shahar Keinan, Igor Kurnikov, Aaron Aponick and Ellen M. Zimmermann   Pages 2543 - 2548 ( 6 )

Abstract:


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.

Affiliation:

Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel., Department of Medicine, University of Florida, Gainesville, FL 32608, USA.



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