Computational modeling and in-vitro/in-silico correlation of phospholipid-based prodrugs for targeted drug delivery in inflammatory bowel disease

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

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Targeting drugs to the inflamed intestinal tissue(s) represents a major advancement in the treatment of inflammatory bowel disease (IBD). In this work we present a powerful in-silico modeling approach to guide the molecular design of novel prodrugs targeting the enzyme PLA2, which is overexpressed in the inflamed tissues of IBD patients. The prodrug consists of the drug moiety bound to the sn-2 position of phospholipid (PL) through a carbonic linker, aiming to allow PLA2 to release the free drug. The linker length dictates the affinity of the PL-drug conjugate to PLA2, and the optimal linker will enable maximal PLA2-mediated activation. Thermodynamic integration and Weighted Histogram Analysis Method (WHAM)/Umbrella Sampling method were used to compute the changes in PLA2 transition state binding free energy of the prodrug molecule (∆∆Gtr) associated with decreasing/increasing linker length. The simulations revealed that 6-carbons linker is the optimal one, whereas shorter or longer linkers resulted in decreased PLA2-mediated activation. These in-silico results were shown to be in excellent correlation with experimental in-vitro data. Overall, this modern computational approach enables optimization of the molecular design of novel prodrugs, which may allow targeting the free drug specifically to the diseased intestinal tissue of IBD patients.

Original languageEnglish
Pages (from-to)1021-1028
Number of pages8
JournalJournal of Computer-Aided Molecular Design
Volume31
Issue number11
DOIs
StatePublished - 1 Nov 2017

Keywords

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

ASJC Scopus subject areas

  • Drug Discovery
  • Computer Science Applications
  • Physical and Theoretical Chemistry

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