COSMOperm: Mechanistic Prediction of Passive Membrane Permeability for Neutral Compounds and Ions and Its pH Dependence

Abstract

We present a new and entirely mechanistic COSMOperm method to predict passive membrane permeabilities for neutral compounds, as well as anions and cations. The COSMOperm approach is based on compound-specific free energy profiles within a membrane of interest from COSMO-RS (conductor-like screening model for realistic solvation) calculations. These are combined with membrane layer-specific diffusion coefficients, for example, in the water phase, the polar head groups, and the alkyl tails of biochemical phospholipid bilayers. COSMO-RS utilizes first-principle quantum chemical structures and physically sound intermolecular interactions (electrostatic, hydrogen bond, and van der Waals). For this reason, it is unbiased toward different application scenarios, such as in cosmetics and industrial chemical or pharmaceutical industries. A fully predictive calculation of passive permeation through phospholipid bilayer membranes results in a performance of r 2 = 0.92; rmsd = 0.90 log10 units for neutral compounds and anions, as compared to gold standard black lipid membrane experiments. It will be demonstrated that new membrane types can be generated by the related COSMOplex method and directly used for permeability studies by COSMOperm.

Modeling of SGLT1 in Reconstituted Systems Reveals Apparent Ion-Dependencies of Glucose Uptake and Strengthens the Notion of Water-Permeable Apo States

“…A deviation of about 1 log unit between an experimentally determined and predicted p -value is normal when using COSMOtherm to calculate the membrane permeability of neutral solutes ( Schwobel et al, 2020 ). For glucose the predicted value (listed in Table 4 ) and the experimentally determined value were in good agreement (P exp = 3.0⋅10 −13 m/s ( Brunner et al, 1980 ); P pred = 2.5⋅10 −13 m/s).…”

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…Unsurprisingly, the permeation of small molecules through the lipid bilayer was among the first membrane-related topics studied through MD simulation, e.g., in 2004, Bemporad et al [149] studied permeation of small organic molecules like benzene or ethanol, and in older studies, Marrink and Berendsen (1994) studied permeation of water [564]. A significant amount of work has been performed to predict the permeability of small molecules through lipid bilayers using various molecular modeling methods and theoretical tools [565][566][567][568][569][570][571][572][573][574]; this includes new computational methodologies, developed specifically for the study of membrane permeability [575][576][577]. A web server and database PerMM is dedicated to gathering experimental and computational data related to small molecule membrane partitioning and translocation [578].…”

Modeling the Percutaneous Absorption of Solvent-deposited Solids Over a Wide Dose Range

“…[62][63][64] Continuously improving methods for molecular simulations of structured lipids offer promise in this area. [64][65][66] Notably, at least one method offers the capability for non specialists to mechanistically study the impact of solute-membrane interactions on membrane permeability. 64,66 Considering that the Model 3 prediction of the underlying membrane permeability of moderately lipophilic solutes in the SC has not improved substantially since Potts and Guy's 1992 correlation 49 (c.f.…”