<i>In silico</i> screening of drug candidates for thermoresponsive liposome formulations

Balouch, Martin; Šrejber, Martin; Šoltys, Marek; Janská, Petra; Štěpánek, František; Berka, Karel

doi:10.1039/d0me00160k

Cited by 6 publications

(6 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, 6 the permeability and partitioning coefficients of 56 APIs from the DrugBank database were calculated and sorted into the LBCS diagram. Out of these, four APIs were identified as particularly poorly permeating: allosamidin, azacitidine, decitabine, and cytarabine.…”

Section: Results and Discussionmentioning

confidence: 99%

“…For the purpose of the present work, the membrane with a fixed composition (DPPC/DPPG/cholesterol = 75:10:15 mol %) at 293 K was used as the permeation barrier. The lipid bilayer structure was obtained by molecular dynamics (MD) simulations, as described in detail in our recent work . Briefly, a membrane bilayer containing 128 preordered lipid molecules was created by an in-house script.…”

Section: Methodsmentioning

confidence: 99%

“…The lipid bilayer structure was obtained by molecular dynamics (MD) simulations, as described in detail in our recent work. 6 Briefly, a membrane bilayer containing 128 preordered lipid molecules was created by an in-house script. Slipids 27 parameters and the TIP3P 28 water model were used for the simulation, and the membrane was simulated at 293 K under periodic boundary conditions for approx.…”

Section: Methodsmentioning

confidence: 99%

“…The lipid/water partitioning coefficient should be sufficiently high to allow the API to overcome the energy barrier represented by the lipid bilayer but sufficiently low to prevent the API from being trapped in the membrane. The phenomena of API partitioning and permeability were investigated computationally and validated experimentally in our recent publication . Systematic rules for the formulability of small-molecule APIs in liposomes have been proposed using the liposome biochemical classification system (LBCS).…”

Section: Introductionmentioning

confidence: 99%

“…The phenomena of API partitioning and permeability were investigated computationally and validated experimentally in our recent publication. 6 Systematic rules for the formulability of small-molecule APIs in liposomes have been proposed using the liposome biochemical classification system (LBCS). LBCS was designed as a two-dimensional (2D) diagram with approximative areas for the partitioning and permeation constants for each pair of API and lipid bilayer composition that enable or prevent successful liposome formulation.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Computational Prodrug Design Methodology for Liposome Formulability Enhancement of Small-Molecule APIs

et al. 2023

Self Cite

View full text Add to dashboard Cite

Encapsulation into liposomes is a formulation strategy that can improve efficacy and reduce side effects of active pharmaceutical ingredients (APIs) that exhibit poor biodistribution or pharmacokinetics when administered alone. However, many APIs are unsuitable for liposomal formulations intended for parenteral administration due to their inherent physicochemical properties�lipid bilayer permeability and water−lipid equilibrium partitioning coefficient. Too high permeability results in premature leakage from liposomes, while too low permeability means the API is not able to pass across biological barriers. There are several options for solving this issue: (i) change of the lipid bilayer composition, (ii) addition of a permeability enhancer, or (iii) modification of the chemical structure of the API to design a prodrug. The latter approach was taken in the present work, and the effect of small changes in the molecular structure of the API on its permeation rate across a lipidic bilayer was systematically explored utilizing computer simulations. An in silico methodology for prodrug design based on the COSMOperm approach has been proposed and applied to four APIs (abiraterone, cytarabine, 5-fluorouracil, and paliperidone). It is shown that the addition of aliphatic hydrocarbon chains via ester or amide bonds can render the molecule more lipophilic and increase its permeability by approximately 1 order of magnitude for each 2 carbon atoms added, while the formation of fructose adducts can provide a more hydrophilic character to the molecule and reduce its lipid partitioning. While partitioning was found to depend only on the size and type of the added group, permeability was found to depend also on the added group location. Overall, it has been shown that both permeability and lipid partitioning coefficient can be systematically shifted into the desired liposome formulability window by appropriate group contributions to the parental drug. This can significantly increase the portfolio of APIs for which liposome or lipid nanoparticle formulations become feasible.

show abstract

Section: Results and Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%