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