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

Arik Dahan, Shimon Ben-Shabat, Noa Cohen, Shahar Keinan, Igor Kurnikov, Aaron Aponick, Ellen M. Zimmermann

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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.

Original languageEnglish
Pages (from-to)2543-2548
Number of pages6
JournalCurrent Topics in Medicinal Chemistry
Volume16
Issue number23
DOIs
StatePublished - 1 Sep 2016

Keywords

  • Drug targeting
  • Inflammatory bowel disease (IBD)
  • Molecular dynamics
  • Phospholipase A (PLA)
  • Prodrugactivating enzyme
  • Thermodynamic integration
  • Umbrella sampling/WHAM methods

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