Mechanistic Insights into Passive Membrane Permeability of Drug-Like Molecules from a Weighted Ensemble of Trajectories

Passive permeability of a drug-like molecule is a critical assay early in a drug discovery campaign that informs a medicinal chemist how well a compound can traverse biological membranes, such as gastrointestinal epithelial or restrictive organ barriers, so it can perform a specific therapeutic function. However, the challenge that remains is the development of a method, experimental or computational, which can both determine the permeation rate and provide mechanistic insights into the transport process to help with the rational design for any given molecule. Typically, one of three methods are used to measure membrane permeability: (1) experimental permeation assays acting on either artificial or natural membranes; (2) quantitative structure-permeability relationship (QSPR) models that rely on experimental values of permeability or related pharmacokinetic properties of a range of molecules to infer those for new molecules; (3) estimates of permeability from the Smoluchowski equation, where free energy and diffusion profiles along the membrane normal are taken as input from large-scale molecular dynamics simulations. While all these methods provide estimates of permeation coefficients, they provide very little information for guiding rational drug design. In this study, we employ a highly parallelizable weighted ensemble (WE) path sampling strategy, empowered by cloud computing techniques, to generate unbiased permeation pathways and permeability coefficients for a set of drug-like molecules across a neat 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) membrane bilayer. Our WE method predicts permeability coefficients that compare well to experimental values from an MDCK-LE cell line and PAMPA assays for a set of drug-like amines of varying size, shape, and flexibility. Our method also yields a series of continuous permeation pathways weighted and ranked by their associated probabilities. Taken together, the ensemble of reactive permeation pathways, along with the estimate of the permeability coefficient, provides a clearer picture of the microscopic underpinnings of small molecule membrane permeation.

The Trend of Permeability of Loess in Yili, China, under Freeze–Thaw Cycles and Its Microscopic Mechanism

Loess landslides induced by the freeze–thaw effect frequently occur in Yili, China. Freeze–thaw cycles cause indelible changes in the soil microstructure, affecting its permeability. This study investigated the impacts of freeze–thaw cycles on the permeability of Yili loess using permeability tests on undisturbed (virgin, in situ) and remolded loess samples taken before and after freeze–thaw cycles. Scanning electron microscopy and nuclear magnetic resonance techniques were utilized to investigate the microscopic mechanism of the freeze–thaw process on the loess. Grey relation analysis (GRA) was employed to analyze the correlation between macroscopic permeability and microscopic parameters (maxi. radius, eccentricity, fractal dimension, directional probability entropy, and porosity). The results revealed that the permeability and all the microstructure parameters have roughly shown the same trend: “fluctuation–towards equilibrium–stability”. Firstly, the permeability coefficients of original and remolded loess experienced three and two peaked–trends, respectively, before 30 freeze–thaw cycles. The trends eventually stabilized within 30–60 freeze–thaw cycles. Increased number of freeze–thaw cycles disintegrated large particles in undisturbed loess into medium–sized particles, and particle shapes became more uncomplicated. Medium–sized particles in the remolded loess agglomerated to larger particles with more complex shapes. Furthermore, the overall porosity of the originally undisturbed loess decreased, and large and medium–sized pores transformed into small pores and micropores. In contrast, the overall porosity of remolded loess increased. Finally, the results revealed that permeability coefficients of the undisturbed and remolded loess became closely related with eccentricity and porosity, respectively. This study provides a reference for preventing and governing the loess landslides induced by the freeze–thaw cycles and permeability reduction in construction on loess in seasonally frozen areas in Yili.

Permeability of Buccal Mucosa

The buccal mucosa provides an alternative route of drug delivery that can be more beneficial compared to other administration routes. Although numerous studies and reviews have been published on buccal drug delivery, an extensive review of the permeability data is not available. Understanding the buccal mucosa barrier could provide insights into the approaches to effective drug delivery and optimization of dosage forms. This paper provides a review on the permeability of the buccal mucosa. The intrinsic permeability coefficients of porcine buccal mucosa were collected. Large variability was observed among the published permeability data. The permeability coefficients were then analyzed using a model involving parallel lipoidal and polar transport pathways. For the lipoidal pathway, a correlation was observed between the permeability coefficients and permeant octanol/water partition coefficients (Kow) and molecular weight (MW) in a subset of the permeability data under specific conditions. The permeability analysis suggested that the buccal permeation barrier was less lipophilic than octanol. For the polar pathway and macromolecules, a correlation was observed between the permeability coefficients and permeant MW. The hindered transport analysis suggested an effective pore radius of 1.5 to 3 nm for the buccal membrane barrier.

Study on Non-Darcian Flow in Interlayer Shear Weakness Zones in the Basalt by High-Pressure Packer Tests

The interlayer shear weakness zone (ISWZ) is a special structural plane with different widths and spacing in stratified rock masses, it has higher permeability compared with surrounding rocks which is a risk factor for the safety of the hydropower station project. The high-pressure packer test (HPPT) by step injection is always applied to characterize the permeability of ISWZ. However, the non-Darcian flow is easy to appear under high pressure, which makes the Darcy law model no longer applicable. In this study, two non-Darcian flow analytical methods for confined aquifer were proposed to investigate the non-Darcian flow permeability parameters. The equivalent permeability coefficients of different non-Darcian models were derived as well. The in situ tests were conducted on the ISWZs at the Baihetan hydropower station to verify the proposed methods. The results indicate that the flow is non-Darcian flow in the test section from integrity to destruction during the whole HPPT process. Izbash’s law has a better fit than Forchheimer’s law in this complicated test situation. The equivalent permeability coefficients after destruction are one or two orders of magnitude larger than those before. Meanwhile, it is necessary to pay attention to the increased difference of two expressions of the equivalent permeability coefficients under higher gradient (i) or velocity (v). In general, these methods can be used to evaluate the characteristic of ISWZ to analyze the impact on engineering stability.

The Slotted Tube Overlay Geotextile in Tailing Pond Radial Seepage Test Model and Analysis of the Permeation Characteristics

Slotted tube drainage system plays an important role in reducing the wetting line of tailing dam. In the past studies, the permeability coefficient of geotextile was measured separately based on one-dimensional test, and the permeability characteristics of the whole system of the slotted tube overlay geotextile were rarely studied. Firstly, a set of radial flow test equipment for infiltration system of the slotted tube overlay geotextile is developed in this study. Then, with the aid of the test device, a two-dimensional radial flow test is conducted to investigate the drainage system of the slotted tube overlay geotextile before and after blocking by tailing sands, with considering different water head difference and the number of geotextile layers. By the two-dimensional radial flow test, it can be concluded that (1) the permeability coefficients of the slotted tube overlay geotextile before and after blocking all have a slight upward trend with the increase of water head difference; (2) with increasing the number of geotextile layers, the permeability coefficients before and after blocking increase first and then decrease, which approaching its minimum value at about two layers; (3) under the seepage pressure, some particles might attach to or stay in geotextile. Therefore, the permeability coefficient of the slotted tube overlay geotextile after blocking is significantly smaller than that before blocking. This study offers the insight to the further research on the permeation characteristics of the slotted tube overlay geotextile system.

Hybrid Microporous Polymeric Materials with Outstanding Permeability and Increased Gas Transport Stability: PTMSP Aging Prevention by Sorption of the Polymerization Catalyst on HCPS

The influence of hyper-crosslinked polystyrene (HCPS) MacronetTM MN200 on the gas transport properties and aging of the highly permeable glassy polymer poly(1-trimethylsilyl-1-propyne) (PTMSP) was studied and analyzed in detail. The gas transport characteristics of dense PTMSP membranes containing 0–10.0 wt % HCPS were studied. It was shown that the introduction of a small amount of HCPS into the PTMSP matrix led to a 50–60% increase of the permeability coefficients of the material for light gases (N2, O2, CO2) and slowed down the deterioration of polymer transport properties over time. The lowest reduction in gas permeability coefficients (50–57%) was found for PTMSP containing HCPS 5.0 wt % after annealing at 100 °C for 300 h. It was found that HCPS sorbed residues of tantalum-based polymerization catalyst from PTMSP. In order to investigate the influence of catalysts on transport and physical properties of PTMSP, we purified the latter from the polymerization catalyst by addition of 5 wt % HCPS into polymer/chloroform solution. It was shown that sorption on HCPS allowed for almost complete removal of tantalum compounds from PTMSP. The membrane made of PTMSP purified by HCPS demonstrated more stable transport characteristics compared to the membrane made of the initial polymer. HCPS has a complex effect on the aging process of PTMSP. The introduction of HCPS into the polymer matrix not only slowed down the physical aging of PTMSP, but also reduced chemical aging due to removal of active reagents.

Transport Characteristics of Plasma Membranes of PK-15 Passaged Cells

The values of permeability coefficients to water molecules and cryoprotectants are demanded to select the optimal duration of exposure of cells in cryoprotective media at the stage of their preparation for cryopreservation, as well as to find optimal cooling and warming rates during the freeze-thawing of cell suspensions. The necessary numerical values of such cell parameters as the osmotically inactive volume α and the surface-area-to-volume ratio γ were obtained for the analytical evaluation of the permeability coefficients of the PK-15 cells’ plasma membranes using physico-mathematical modelling. The permeability coefficients kp of the plasma membranes of PK-15 cells to 1,2-PD, EG, DMSO and glycerol cryoprotectants molecules, as well as the filtration coefficients Lp to water molecules at temperatures of 25, 15 and 5°C were determined by approximating the experimental data of the change in relative volume of cells on exposure time in the studied solutions by theoretical curves calculated on the basis of physical and mathematical model of passive transport of water and permeable substances under the condition of their maximum coincidence. The value of the activation energy of the transmembrane transfer of molecules of these substances is calculated

Development and evaluation of two-parameter linear free energy models for the prediction of human skin permeability coefficient of neutral organic chemicals

The experimental values of skin permeability coefficients, required for dermal exposure assessment, are not readily available for many chemicals. The existing estimation approaches are either less accurate or require many parameters that are not readily available. Furthermore, current estimation methods are not easy to apply to complex environmental mixtures. We present two models to estimate the skin permeability coefficients of neutral organic chemicals. The first model, referred to here as the 2-parameter partitioning model (PPM), exploits a linear free energy relationship (LFER) of skin permeability coefficient with a linear combination of partition coefficients for octanol–water and air–water systems. The second model is based on the retention time information of nonpolar analytes on comprehensive two-dimensional gas chromatography (GC × GC). The PPM successfully explained variability in the skin permeability data (n = 175) with R2 = 0.82 and root mean square error (RMSE) = 0.47 log unit. In comparison, the US-EPA’s model DERMWIN™ exhibited an RMSE of 0.78 log unit. The Zhang model—a 5-parameter LFER equation based on experimental Abraham solute descriptors (ASDs)—performed slightly better with an RMSE value of 0.44 log unit. However, the Zhang model is limited by the scarcity of experimental ASDs. The GC × GC model successfully explained the variance in skin permeability data of nonpolar chemicals (n = 79) with R2 = 0.90 and RMSE = 0.23 log unit. The PPM can easily be implemented in US-EPA’s Estimation Program Interface Suite (EPI Suite™). The GC × GC model can be applied to the complex mixtures of nonpolar chemicals.

Experimental Investigation of Gas Dynamic Effects Using Nanoporous Synthetic Materials as Tight Rock Analogues

To improve the understanding of gas transport processes in tight rocks (e.g., shales), systematic flow tests with different gases were conducted on artificial micro- to nanoporous analogue materials. Due to the rigidity of these systems, fluid-dynamic effects could be studied at elevated pressures without interference of poro-elastic effects. Flow tests with narrow capillaries did not reveal any viscosity anomaly in a confined space down to capillary diameters of 2 µm. Experiments with nanoporous ceramic disks (> 99% Al2O3) conducted at confining pressures from 10 to 50 MPa did not indicate any stress dependence of permeability coefficients. Analysis of the apparent permeability coefficients over a mean gas pressure range from 0.2 to 30.5 MPa showed essentially linear Klinkenberg trends with no indication of second-order slip flow. The Klinkenberg-corrected permeability coefficients measured with helium were consistently higher than those measured with all other gases under the same conditions. This “helium anomaly” was, however, less pronounced than the same effect observed in natural rocks, indicating that it is probably not related to fluid-dynamic effects but rather to gas–solid interactions (e.g., sorption). Permeability tests with CO2 on the nanoporous membrane show significant deviations from the linear Klinkenberg trend around the critical point. This is due to the drastic changes of the thermodynamic properties, in particular the isothermal compressibility, in this pressure and temperature range. Helium pycnometry, mercury intrusion porosimetry and low-pressure nitrogen sorption showed good agreement in terms of porosity (~ 28%) and the most prominent pore diameter (~ 68.5 nm).