Molecular Modeling-Guided Design of Phospholipid-Based Prodrugs

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.

Lipase Catalyzed Acidolysis for Efficient Synthesis of Phospholipids Enriched with Isomerically Pure cis-9,trans-11 and trans-10,cis-12 Conjugated Linoleic Acid

“…Vertical bars represent SD, n = 3. 3 22.7 ± 3.9 7 2.6 ± 0.4 5 3.4 ± 0.4 10 2.6 ± 0.4 5 3.4 ± 0.4 10 38.2 ± 3.4 11,12 11.7 ± 0.6 20 50.1 ± 4.0 19 53.2 ± 1.0 14 30.9 ± 1.2 18 15.9 ± 2.2 22 TLL 5.9 ± 0.4 4 5.3 ± 0.5 8 3.1 ± 0.6 3,5 nd 37.1 ± 0.4 12 13.9 ± 0.3 17 49.0 ± 0.7 19 42.7 ± 0.5 15 30.6 ± 1.1 18 26.7 ± 1.5 23 1 Results refers to 24 h of the acidolysis reaction, condition are given in Figure 2. The values are mean ± SD based on three independent experiments.…”

“…This type of phospholipid conjugate plays a role of lipophilic prodrug where glycerophosphocholine is esterified in sn-1 or sn-2 position with the biologically active molecules, mainly with those that do not occur 2 of 22 naturally in the phospholipid structure. Such lipophilization of biologically active compounds can to overcome the biological barriers, improves bioavailability and the drug safety profile, facilitating formulation development and drug administration [11].…”

Enzyme Models—From Catalysis to Prodrugs

“…On the other hand, hydrolytic enzymes such as phospholipase A 2 (PLA 2 ) are responsible for the hydrolysis of phospholipid-based prodrug at sn -2 positioned fatty acid; therefore, conjugation of phosphate or glyceride to the drug results in the enzymatic activation of the designed prodrug and the liberation of the free drug moiety. Activity of PLA 2 towards phospholipid-based prodrugs can be determined by different molecular modeling methods such as molecular docking and MD simulations to point out the structural adjustments of the conjugated moiety and their length that are required to get the highest degree of prodrug activation [ 97 , 98 ]. Another example of hydrolytic enzymes are human carboxylesterase (hCE) types 1 and 2 that hydrolyze prodrugs with ester bonds such as epalrestat and natural antioxidant products used for diabetes complications.…”

Lipids and Lipid-Processing Pathways in Drug Delivery and Therapeutics

“…Linking the drug directly to the sn-2 PL position showed the absence of PLA 2 -mediated activation [58]; however, once the linker was introduced the activation of the prodrug was possible [59][60][61]. Novel computational analysis was used to optimize the prodrug design (linker length) [62][63][64]. For instance, PL-indomethacin prodrug was orally administered to rats and the prodrug with 5-carbon linker (DP-155, Table 1) showed a 20-fold increase in free drug vs. the PL-indomethacin prodrug with the 2-carbon linker.…”