Mechanism of the enhancing effect of glycyrrhizin on nifedipine penetration through a lipid membrane.

The saponin glycyrrhizin from liquorice root shows the ability to enhance the therapeutic activity of other drugs when used as a drug delivery system. Due to its amphiphilic properties, glycyrrhizin can form self-associates (dimers, micelles) and supramolecular complexes with a wide range of hydrophobic drugs, which leads to an increase in their solubility, stability and bioavailability. That is why the mechanism of the biological activity of glycyrrhizin is of considerable interest and has been the subject of intensive physical and chemical research in the last decade. Two mechanisms have been proposed to explain the effect of glycyrrhizin on drug bioavailability, namely, the increase in drug solubility in water and enhancement of the membrane permeability. Interest in the membrane-modifying ability of glycyrrhizic acid (GA) is also growing at present due to its recently discovered antiviral activity against SARS-CoV-2 Bailly and Vergoten (2020) [1]. In the present study, the passive permeability of the DOPC lipid membrane for the calcium channel blocker nifedipine was elucidated by parallel artificial membrane permeability assay (PAMPA) and full atomistic molecular dynamics (MD) simulation with free energy calculations. PAMPA experiments show a remarkable increase in the amount of nifedipine (NF) permeated with glycyrrhizin compared to free NF. In previous studies, we have shown using MD techniques that glycyrrhizin molecules can integrate into the lipid bilayer. In this study, MD simulation demonstrates a significant decrease in the energy barrier of NF penetration through the lipid bilayer in the presence of glycyrrhizin both in the pure DOPC membrane and in the membrane with cholesterol. This effect can be explained by the formation of hydrogen bonds between NF and GA in the middle of the bilayer.

[Aggregation function of platelets in persons with arterial hypertension and abdominal obesity].

In patients with arterial hypertension (AH) accompanied by abdominal obesity (AO) increase in platelets adhesive and aggregation functions was noted in vitro and in vivo. The cause of these disturbances is blood serum and platelets lipid peroxidation activation, increase in synthesis of Willebrand's factor in a vascular wall, and intensification of thromboxane production in platelets. Activation of thromboplastin production is the main cause of increase in blood coagulation in patients with AH and AO.

Structural and entropic insights into the nature of the random-close-packing limit.

Disordered packings of equal sized spheres cannot be generated above the limiting density (fraction of volume occupied by the spheres) of rho approximately 0.64 without introducing some partial crystallization. The nature of this "random-close-packing" limit (RCP) is investigated by using both geometrical and statistical mechanics tools applied to a large set of experiments and numerical simulations of equal-sized sphere packings. The study of the Delaunay simplexes decomposition reveals that the fraction of "quasiperfect tetrahedra" grows with the density up to a saturation fraction of approximately 30% reached at the RCP limit. At this limit the fraction of aggregate "polytetrahedral" structures (made of quasiperfect tetrahedra which share a common triangular face) reaches it maximal extension involving all the spheres. Above the RCP limit the polytetrahedral structure gets rapidly disassembled. The entropy of the disordered packings, calculated from the study of the local volume fluctuations, decreases uniformly and vanishes at the (extrapolated) limit rho(Kappa) approximately 0.66 . Before such limit, and precisely in the range of densities between 0.646 and 0.66, a phase separated mixture of disordered and crystalline phases is observed.

Polytetrahedral nature of the dense disordered packings of hard spheres.

We study the structure of numerically simulated hard sphere packings at different densities by investigating local tetrahedral configurations of the spheres. Clusters of tetrahedra adjacent by faces present relatively dense aggregates of spheres atypical for crystals. The number of spheres participating in such polytetrahedral configurations increases with densification of the packing, and at the Bernal's limiting density (the packing fraction around 0.64) all spheres of the packing become involved in such tetrahedra. Thus the polytetrahedral packing cannot provide further increase in the density, and alternative structural change (formation of crystalline nuclei) begins henceforth.

An algorithm for three-dimensional Voronoi S-network.

The paper presents an algorithm for calculating the three-dimensional Voronoi-Delaunay tessellation for an ensemble of spheres of different radii (additively-weighted Voronoi diagram). Data structure and output of the algorithm is oriented toward the exploration of the voids between the spheres. The main geometric construct that we develop is the Voronoi S-network (the network of vertices and edges of the Voronoi regions determined in relation to the surfaces of the spheres). General scheme of the algorithm and the key points of its realization are discussed. The principle of the algorithm is that for each determined site of the network we find its neighbor sites. Thus, starting from a known site of the network, we sequentially find the whole network. The starting site of the network is easily determined based on certain considerations. Geometric properties of ensembles of spheres of different radii are discussed, the conditions of applicability and limitations of the algorithm are indicated. The algorithm is capable of working with a wide variety of physical models, which may be represented as sets of spheres, including computer models of complex molecular systems. Emphasis was placed on the issue of increasing the efficiency of algorithm to work with large models (tens of thousands of atoms). It was demonstrated that the experimental CPU time increases linearly with the number of atoms in the system, O(n).

Computer simulation study of intermolecular voids in unsaturated phosphatidylcholine lipid bilayers.

Computer simulation of the liquid crystalline phase of five different hydrated unsaturated phosphadidylcholine (PC) lipid bilayers, i.e., membranes built up by 18:0/18:1omega9cis PC, 18:0/18:2omega6cis PC, 18:0/18:3omega3cis PC, 18:0/20:4omega6cis PC, and 18:0/22:6omega3cis PC molecules have been performed on the isothermal-isobaric ensemble at 1 atm and 303 K. (The notation n:domegapcis specifies the lipid tails: n refers to the total number of carbon atoms in the chain, d is the number of the methylene-interrupted double bonds, p denotes the number of carbons between the chain terminal CH(3) group and the nearest double bond, and cis refers to the conformation around the double bonds.) The characteristics of the free volume in these systems have been analyzed by means of a generalized version of the Voronoi-Delaunay method [M. G. Alinchenko et al., J. Phys. Chem. B 108, 19056 (2004)]. As a reference system, the hydrated bilayer of the saturated 14:014:0 PC molecules (dimyristoylphosphatidylcholine) has also been analyzed. It has been found that the profiles of the fraction of the free volume across the membrane exhibit a rather complex pattern. This fine structure of the free volume fraction profiles can be interpreted by dividing the membrane into three separate major zones (i.e., zones of the aqueous, polar, and apolar parts of the membrane) and defining five subzones within these zones according to the average position of various atomic groups in the membrane. The fraction of the free volume in the middle of the membrane is found to increase with increasing unsaturation of the sn-2 chain of the lipid molecule. This is due to the fact that with increasing number of methylene-interrupted double bonds the lipid tails become more flexible, and hence they do not extend to the middle of the membrane. It is found that there are no broad enough preformed channels in the bilayers through which small penetrants, such as water molecules, can readily go through; however, the existing channels can largely facilitate the permeation of these molecules.

Voronoi-Delaunay analysis of voids in systems of nonspherical particles.

The Voronoi network is known to be a useful tool for the structural description of voids in the packings of spheres produced by computer simulations. In this article we extend the Voronoi-Delaunay analysis to packings of nonspherical convex objects. Main properties of the Voronoi network, which are known for systems of spheres, are valid for systems of any convex objects. A general numerical algorithm for calculation of the Voronoi network in three dimensions is proposed. It is based on the calculation of the trajectory of the imaginary empty sphere of variable size, moving inside a system (the Delaunay empty sphere method). Analysis of voids is presented for an ensemble of random straight lines and for a molecular dynamics model of liquid crystal. The spatial distribution of voids and a simple percolation analysis are obtained. The distributions of the bottleneck radii and the radii of spheres inscribed in the voids are calculated.