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

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

Volume: 16 Issue: 23

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

Affiliation:

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

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.

Cite this article as:

Dahan Arik, Ben-Shabat Shimon, Cohen Noa, Keinan Shahar, Kurnikov Igor, Aponick Aaron and Zimmermann M. Ellen, Phospholipid-Based Prodrugs for Drug Targeting in Inflammatory Bowel Disease: Computational Optimization and In-Vitro Correlation, Current Topics in Medicinal Chemistry 2016; 16 (23) . https://dx.doi.org/10.2174/1568026616666160414122913