Quantitative modeling of selective lysosomal targeting for drug design

Abstract

Lysosomes are acidic organelles and are involved in various diseases, the most prominent is malaria. Accumulation of molecules in the cell by diffusion from the external solution into cytosol, lysosome and mitochondrium was calculated with the Fick-Nernst-Planck-equation. The cell model considers the diffusion of neutral and ionic molecules across biomembranes, dissociation to mono-or bivalent ions, adsorption to lipids, and electrical attraction or repulsion. Based on simulation results, high and selective accumulation in lysosomes was found for weak mono-and bivalent bases with intermediate to high log Kow. These findings were validated with experimental results and by a comparison to the properties of antimalarial drugs in clinical use. For ten active compounds, nine were predicted to accumulate to a greater extent in lysosomes than in other organelles, six of these were in the optimum range predicted by the model and three were close. Five of the antimalarial drugs were lipophilic weak dibasic compounds. The predicted optimum properties for a selective accumulation of weak bivalent bases in lysosomes are consistent with experimental values and are more accurate than any prior calculation. This demonstrates that the cell model can be a useful tool for the design of effective lysosome-targeting drugs with minimal off-target interactions.

Development of a Population Pharmacokinetic Model Characterizing the Tissue Distribution of Azithromycin in Healthy Subjects

“…In particular, our calculation of AZM accumulation ratios in the subcellular compartments of PMLs are in agreement with the ratios predicted using another subcellular disposition model (23). In addition to the pH-dependent accumulation of AZM in acidic cell compartments, it has also been shown that the drug can bind in its protonated form to negatively charged phospholipids, which further increases its accumulation in tissues (22,38).…”

“…Equation 6 can also be used to compute the differences in f unionized in different cell compartments, e.g., between the cytosol of PMLs (pH ϳ7 [23,24]) and the lysosomes located within PMLs (pH ϳ5 [23,25]). Given that f unionized in the lysosomes is very low (0.000013), we assumed that once AZM is protonated in the acidic environment of lysosomes, it is trapped and thus no longer available for direct exchange with the plasma compartment.…”

Toward a Unified Model of Passive Drug Permeation II: The Physiochemical Determinants of Unbound Tissue Distribution with Applications to the Design of Hepatoselective Glucokinase Activators

“…LC-MS/MS analysis was conducted on a Sciex Triple Quad 4000 mass spectrometer (turbospray ionization source) with a (Trapp and Horobin, 2005;Trapp et al, 2008). Key components of the model are illustrated in Fig.…”

Challenges of Antibacterial Discovery

“…Recent modeling studies by Trapp and coauthors have approached the flux of neutral and ionic compounds into plants and animal cells and organelles by using a dynamic cell model based on the "Fick-Nernst-Planck" equation (a combination of Fick's first law and the Nernst-Planck equation describing the electrochemical potential) (162,(365)(366)(367). Adapting and enhancing this model, Zarfl and colleagues simulated accumulation in cells of a group of antibacterial sulfonamides based on various assumptions about the permeating capability of the anionic species of the compounds (402).…”