Molecular Modeling-Guided Design of Phospholipid-Based Prodrugs.

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

doi:10.3390/ijms20092210

Abstract

The lipidic prodrug approach is an emerging field for improving a number of biopharmaceutical and drug delivery aspects. Owing to their structure and nature, phospholipid (PL)-based prodrugs may join endogenous lipid processing pathways, and hence significantly improve the pharmacokinetics and/or bioavailability of the drug. Additional advantages of this approach include drug targeting by enzyme-triggered drug release, blood–brain barrier permeability, lymphatic targeting, overcoming drug resistance, or enabling appropriate formulation. The PL-prodrug design includes various structural modalities-different conjugation strategies and/or the use of linkers between the PL and the drug moiety, which considerably influence the prodrug characteristics and the consequent effects. In this article, we describe how molecular modeling can guide the structural design of PL-based prodrugs. Computational simulations can predict the extent of phospholipase A2 (PLA2)-mediated activation, and facilitate prodrug development. Several computational methods have been used to facilitate the design of the pro-drugs, which will be reviewed here, including molecular docking, the free energy perturbation method, molecular dynamics simulations, and free density functional theory. Altogether, the studies described in this article indicate that computational simulation-guided PL-based prodrug molecular design correlates well with the experimental results, allowing for more mechanistic and less empirical development. In the future, the use of molecular modeling techniques to predict the activity of PL-prodrugs should be used earlier in the development process.

Highlights

Prodrugs are inactive drug derivatives that are enzymatically or chemically converted to the active drug moiety in-vivo [1,2]
In the case of the PL-diclofenac and PL-indomethacin prodrugs, the computational method permits the optimization of the chemical structure of the molecular linker connecting the drug moiety to the PL, and reducing the amount of chemical synthesis needed for developing the effective PL-prodrugs
Novel molecular modeling calculations are employed to determine the affinity of the Phospholipase A2 (PLA2) enzyme towards PL-prodrugs, and to provide information about the required prodrug structure modifications in order to accomplish optimal enzyme activation; the molecular dynamics (MD) simulations were proven to be a very useful tool to achieve this aim

Summary

Introduction

Prodrugs are inactive drug derivatives that are enzymatically or chemically converted to the active drug moiety in-vivo [1,2]. Molecular docking is a fast routine method in the optimization of drug screening and design; the accuracy of such simulations is low (~20%) [20,21] The reasons for this lack of precision are numerous, and include the use of a small database of molecules, the wrong choice of docking pose, the incorrect binding site of the target protein, a high docking score but unsuccessful molecular dynamics (MD) simulation, and more; this should be taken into account before performing molecular docking studies [22,23]. Physics-based computerized models, even though complex and time consuming, provide more accurate predictions, in comparison to empirical models such as docking (~80%) These include quantum mechanics/molecular mechanics (QM/MM) or free energy perturbation (FEP) methods [20]. The key advantages of molecular dynamics simulations for PL-prodrugs will be presented, as a useful tool in revealing structure-to-function relationship between macromolecules and for examining the conformational ensembles in a biorelevant surrounding

Overview of Phospholipid-Based Prodrugs

Computational Optimization of PL-Prodrug Design

Molecular Docking

Discussion

Conclusions