Predicting a Drug’s Membrane Permeability: A Computational Model Validated With in Vitro Permeability Assay Data

Abstract

Membrane permeability is a key property to consider during the drug design process, and particularly vital when dealing with small molecules that have intracellular targets as their efficacy highly depends on their ability to cross the membrane. In this work, we describe the use of umbrella sampling molecular dynamics (MD) computational modeling to comprehensively assess the passive permeability profile of a range of compounds through a lipid bilayer. The model was initially calibrated through in vitro validation studies employing a parallel artificial membrane permeability assay (PAMPA). The model was subsequently evaluated for its quantitative prediction of permeability profiles for a series of custom synthesized and closely related compounds. The results exhibited substantially improved agreement with the PAMPA data, relative to alternative existing methods. Our work introduces a computational model that underwent progressive molding and fine-tuning as a result of its synergistic collaboration with numerous in vitro PAMPA permeability assays. The presented computational model introduces itself as a useful, predictive tool for permeability prediction.

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

“…All compounds were quantified by UPLC separation and UV detection, and effective permeability (cm/s) was calculated. All UPLC detection protocols and calculation parameters have been previously described (Bennion et al, 2017). …”

“…Each compound was examined in at least three replicates. As above, compound in buffer was quantified by UPLC as previously described (Bennion et al, 2017). Permeability of each compound across inserts not containing cells was examined as a control in each assay plate.…”

“…The efflux ratio was calculated as the ratio of permeability in the B > A direction to permeability in the A > B direction. As above, quantity of compound in buffer was quantified by UPLC as previously described (Bennion et al, 2017). Results are represented as the net flux ratio (NFR), calculated as the efflux ratio in MDR-MDCK cells to efflux ratio in MDCK cells.…”

A Zebrafish Embryo as an Animal Model for the Treatment of Hyperpigmentation in Cosmetic Dermatology Medicine

“…The chorion with pore channel of around 0.5 to 0.7 μm diameter with gap at 1.5 to 2.5 μm intervals, which surrounds the embryo reduces the diffusion rate of small molecules into the embryo [37] (Figure 4). Hydrophobicity affects molecule absorption, bioavailability, hydrophobic molecules-receptor interactions, molecule metabolism and their toxicological endpoints [90,94]. LogP is a measure of molecular hydrophobicity, an important parameter in designing molecules and to determining its quantitative structure-activity relationship (QSAR) [94].…”

“…Hydrophobicity affects molecule absorption, bioavailability, hydrophobic molecules-receptor interactions, molecule metabolism and their toxicological endpoints [90,94]. LogP is a measure of molecular hydrophobicity, an important parameter in designing molecules and to determining its quantitative structure-activity relationship (QSAR) [94]. In particular, with a similar partition coefficient (LogP), the permeability of a smaller molecule is relatively higher than that of a larger molecule, thus allowing a number of smaller molecules to bind to TYR and inhibit its activity as compared to larger molecules.…”