Serum albumin binding

Aqueous solubility is not usually considered a priori as a problem in the drug discovery of acidic compounds. More important issues are (i) the high serum albumin binding of stronger acids, (ii) the very low or nonexistent central nervous system penetration of stronger acids, (iii) the low volumes of distribution of acids limiting these mostly to plasma compartment targets, (iv) the possibility of formation of... 

Hollosy, F., Valko, K., Hersey, A., Nunhuck, S., Keri, G., Bevan, C. Estimation of volume of distribution in humans from high throughput HPLC-based measurements of human serum albumin binding and immobilized artificial membrane partitioning. J. Med. Chem. 2006, 49, 6958-6971. 

This section will provide an overview on ADME models from our group to illustrate our approach for building predictive models on structurally diverse training sets. Datasets for intestinal human absorption and human serum albumin binding are discussed, while models for other relevant ADME properties have also been obtained. Those models, however, do not stand alone but are used in combination with those models tailored for affinity and selectivity in the frame of multidimensional lead optimization. 

Fig. 14.7 Correlation ofVolSurf descriptors with human serum albumin binding affinity. Two submodels indicate their predictive ability to external test sets. Ten compounds were removed by either experimental design on PCA scores (A) or literature proposals (B). Model A 0.558,...

The most frequent protein in the plasma, at around 45 g is albumin. Due to its high concentration, it plays a crucial role in maintaining the blood s colloid osmotic pressure and represents an important amino acid reserve for the body. Albumin has binding sites for apolar substances and therefore functions as a transport protein for long-chain fatty acids, bilirubin, drugs, and some steroid hormones and vitamins. In addition, serum albumin binds Ca "" and Mg "" ions. It is the only important plasma protein that is not glycosylated. 

In 2007, Wichmann et al. [47] applied several COSMO-RS cr-moments as descriptors to model PPB. Unlike the above-mentioned PPB models, which predicted %PPB directly, Wichmann et al. built up a QSAR model to predict human serum albumin binding, log Kt SA (logarithm of %bound/%free), instead. The performance of the log K isa model was reasonable given only four... 

Wichmann, K., Diedenhofen, M., Klamt, A. Prediction of blood-brain partitioning and human serum albumin binding based on COSMO-RS sigma-moments. J. Chem. Inf. Model. 2007, 47,... 

The fatty acids could be carried by proteins by a process similar to the way in which serum albumin binds fatty acid in the bloodstream of mammals. Other types of lipid might be formed into complexes analogous to low-density lipoproteins of the type found in animal tissues, where the lipid core of the lipoprotein is surrounded by a hydrophilic cortex made up of protein, phospholipid, and cholesterol (87). This allows the lipid to be moved in an aqueous environment. The protein of the lipoprotein shell could also act as possible ligands for particular receptors at the membrane of the cell at which the export occurs. The lipoproteins, if they are present, would probably be formed within the endomembrane lumen and would receive the proteins at the endoplasmic reticulum. 

Y Ding, X Zhu, B Lin. Capillary electrophoresis study of human serum albumin binding to basic drugs. Chromatographia 49 343-346, 1999. 

Gunturi, S.B., Narayanan, R. and Khandelwal, A. (2006) In silico ADME modelling 2 Computational models to predict human serum albumin binding affinity using ant colony systems. Bioorganic and Medicinal Chemistry, 14, 4118 129. 

Erostell-Karlsson, A., Remaeus, A., Roos, H., Andersson, K, Borg, P., Hiimalainen, M. and Karlsson, R. (2000) Biosensor analysis of the interaction between immobilized human serum albumin and drug compounds for prediction of human serum albumin binding levels. Journal of Medicinal Chemistry, 43, 1986-1992. 

Hartmann, T Schmitt, J., Rohring, C., Nimptsch, D Noller, J. and Mohr, C. (2006) ADME related profiling in 96 and 384 well plate format — a novel and robust HT-assay for the determination of lipophilicity and serum albumin binding. Current Drug Delivery, 3, 181-192. 

Serum albumin is the most plentiful protein in blood plasma. Each molecule can carry seven fatty acid molecules. They bind in deep crevices in the protein, burying their carbon-rich chains away from the surrounding water. Serum albumin also binds to many other water-insoluble molecules. In particular, serum albumin binds to many drug molecules and can strongly affect the way they are delivered through the body. 

Correlating 3D Structure to Human Serum Albumin Binding... 

Fig. 6. Correlation of VolSurf descriptors with human serum albumin binding affinity for 93 drug-like molecules. Left. Predicted versus experimental -log(K(HSA)) from the final 6 component PLS model. Right PLS loadings showing the importance of VolSurf descriptors to the prediction of human serum albumin binding.

The CR Gd(DTPA)2 is modified by attaching diphenyl cyclohexyl-phosphodiester residue, and its structure is shown in Fig. 12.38. The attached diester residue is a ligand for serum albumin binding sites [204]. 

Although these compounds were extremely potent, they were hampered by serum albumin binding (39, 40). 

The separation technique can be used in two different ways for the measurements of physico-chemical parameters. In one approach the propenies of the compounds are characterised directly from the chromatographic retention which is determined by the interaction of solutes with the stationary and the mobile phases. This approach can be used for lipophilicity determination, measurements of serum albumin binding and estimating the membrane transport of compounds from their retention on immobilised artificial membrane. 

Fig. 12.11. The calibration plot to determine serum albumin binding on an immobilised HSA column (taken from Ref. 192]).

The initial event in the utilization of fat as an energy source is the hydrolysis of triacylglycerols by lipases, an event referred to as lipolysis. The lipase of adipose tissue are activated on treatment of these cells with the hormones epinephrine, norepinephrine, glucagon, and adrenocorticotropic hormone. In adipose cells, these hormones trigger 7TM receptors that activate adenylate cyclase (Section 15,1.3 ). The increased level of cyclic AMP then stimulates protein kinase A, -which activates the lipases by phosphorylating them. Thus, epinephrine, norepinephrine, glucagon, and adrenocorticotropic hormone induce lipolysis (Figure 22.6). In contrast, insulin inhibits lipolysis. The released fatty acids are not soluble in blood plasma, and so, on release, serum albumin binds the fatty acids and serves as a carrier. By these means, free fatty acids are made accessible as a fuel in other tissues. 

Absorbed Cd bound to red blood cells and serum albumin (binding to sulfhydryl groups on proteins is especially strong). 

B. Subfile and N. Thuaud, Determination of tryptophan-human serum albumin binding from retention data and separation of tryptophan enantiomers by high-performance liquid chromatography, J. Litj. Chromatogr., 3 299 (1980). 

R. I. Nazareth, T. D. Sokoloski, D. T. Witiak, and A. T. Hopper, Biological significance of serum albumin binding parameters determined in vitro for clofibrate-related hypolipemic drugs, /. Pfiarm. Sci., 63 203 (1974). 

General regression neural network (GRNN) was introduced by Donald Specht in 1991 [33], and it has been successfully used in pharmacokinetic studies, including human intestinal absorption [34], blood-brain barrier prediction [35], human serum albumin binding [35], milk-plasma ratio [35], and drug clearance [36], Recently it has been applied for the prediction of Tetrahymenapyriformis toxicity [37],... 

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