Journal of Computer-Aided Molecular Design

, Volume 31, Issue 11, pp 1021–1028 | Cite as

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

  • Arik DahanEmail author
  • Milica Markovic
  • Shahar Keinan
  • Igor Kurnikov
  • Aaron Aponick
  • Ellen M. Zimmermann
  • Shimon Ben-Shabat


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.


Drug targeting Inflammatory bowel disease (IBD) Molecular dynamics Phospholipase A2 (PLA2Prodrug Thermodynamic integration Umbrella sampling/WHAM 



This work was funded through the US-Israel Binational Science Foundation (BSF) Grant No: 2015365. This work is a part of Ms. Milica Markovic PhD dissertation.

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interests.


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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health SciencesBen-Gurion University of the NegevBeer-ShevaIsrael
  2. 2.Cloud Pharmaceuticals Inc.Research Triangle ParkUSA
  3. 3.Department of ChemistryUniversity of FloridaGainesvilleUSA
  4. 4.Department of Medicine, Division of GastroenterologyUniversity of FloridaGainesvilleUSA

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