Membrane permeability modeling model structure

Besides Ap, other amphipathic model peptides are also studied using IRRAS. The linear sequence KLAL (KLALKLALKALKAALKLA-NH2) is a model compound to form amphipathic helices, which is able to bind to membranes and to increase the membrane permeability in a structure and target-dependent manner [71,72], Kerth et al. first studied the secondary structure of... 

It was postulated that the aqueous pores are available to all molecular species, both ionic and non-ionic, while the lipoidal pathway is accessible only to un-ionised species. In addition, Ho and co-workers introduced the concept of the aqueous boundary layer (ABL) [9, 10], The ABL is considered a stagnant water layer adjacent to the apical membrane surface that is created by incomplete mixing of luminal contents near the intestinal cell surface. The influence of drug structure on permeability in these domains will be different for example ABL permeability (Paq) is inversely related to solute size, whereas membrane permeability (Pm) is dependent on both size and charge. Using this model, the apparent permeability coefficient (Papp) through the biomembrane may therefore be expressed as a function of the resistance of the ABL and... 

Membrane permeability is one of the most important determinants of pharmacokinetics, not only for oral absorption, but also for renal re-absorption, biliary excretion, skin permeation, distribution to a specific organ and so on. In addition, modification of membrane permeability by formulation is rarely successful. Therefore, membrane permeability should be optimized during the structure optimization process in drug discovery. In this chapter, we give an overview of the physiology and chemistry of the membranes, in vitro permeability models and in silica predictions. This chapter focuses on progress in recent years in intestinal and blood-brain barrier (BBB) membrane permeation. There are a number of useful reviews summarizing earlier work [1-5]. 

Sadowski J, Gasteiger J, Klebe G (1994) Comparison of automatic three-dimensional model builders using 639 X-ray structures. J Chem Inf Comp Sci 34 1000-1008 Stenberg P, Luthman K, Artursson P (1999) Prediction of membrane permeability to peptides from calculated dynamic molecular surface properties. Pharm Res 16 205-212 Stenberg P, Luthman K, Ellens H et al. (1999) Prediction of the intestinal absorption of endothelin receptor antagonists using three theoretical methods of increasing complexity. Pharm Res 16 1520-1526... 

The resulting semi-quantitative model was used in conjunction with structure-based docking and scoring, 3D-QS AR based affinity and selectivity predictions and in silico ADME models to estimate membrane permeability, solubility, and other key properties for the optimization process in this series. Hence, in this as well as in other series, multiple models can be collectively applied for ranking and prioritizing synthesis candidates and focused virtual libraries during advanced stages of multidimensional compound optimization. 

Fig. 7.2 Tlie crystal structure of mammalian Ser/Thr protein phosphatase-1, complexed with the toxin mycrocystin was determined at 2.1 A resolution. PPl has a single domain with a fold, distinct from that of the protein tyrosine phosphatases. The Ser/Thr protein phosphatase-1, is a metalloenzyme with two metal ions positioned at the active site with the help of a p-a-p-o-p scaffold. A dinuclear ion centre consisting of Mn2+ And Fe2+ g situated at the catalytic site that binds the phosphate moiety of the substrate. Ser/Thr phosphatases, PPl and PP2A, are inhibited by the membrane-permeable ocadaic acid and by cyclic hexapeptides, known as microcystins. The toxin molecule is depicted as a ball-and-stick structure. On the left and on the ri t, two different views of the same molecule are shown. Microcystin binds to three distinct regions of the phosphatase to the metaLbinding site, to a hydrophobic groove, and to the edge of a C-terminal groove in the vicinity of the active site. At the surface are binding sites for substrates and inhibitors. These ribbon models are reproduced vnth permission of the authors and Nature from ref. 9.

Liposomes are considered as substantial models for the study of biological membranes. They have many physicochemical properties, such as membranes permeability, osmotic activity, interaction with various solutes, surface characteristics and chemical composition similar to cell membranes. The fluidity of their membranes and their self-closed structure are essential parameters for the study of the biological membrane function. 

These techniques involving the measurement of membrane permeability to a fluid (liquid or gas) lead to a mean pore radius (usually the effective hydraulic radius Th) whose quantitative value is often highly ambiguous. The flux of a fluid through a porous material is sensitive to all structural aspects of the material [129]. Thus, in spite of the simplicity of the method, the interpretation of flux data, even for the simplest case of steady state, is subject to uncertainties and depends on the models and approximations used. 

Most recently these ideas have been combined with a numerical cell model to relate S(q, A, r) to cell structure in plant parenchyma tissue.143 Using PGSE data for apple tissue a value for the plasmalemma membrane permeability was estimated. The application of this numerical cell model to mammalian tissue might enable quantitative interpretation of diffusion weighted contrast in clinical MRI. Table 6 lists a number of other applications of the PGSE method to food-related materials, although few of these studies have attempted to explore systematically the whole of the three-dimensional q—A—r space. 

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