Binding macromolecule

Enantioselective differences in absorption, metaboHsm, clearance, dmg— macromolecule binding affinity, and other factors, which culminate in the observed enantioselective efficacy of chiral dmgs, are considered herein. More inclusive Hsts of optically active dmgs and theit enantioselective differences are available (93). 

Useful data for the hazard assessment may also be obtained from studies on toxicokinetics (including metabolism), in vitro studies on macromolecule binding, from knowledge of the reactivity and electrophilicity of a substance, and from the presence or absence of structural alerts for genotoxicity. 

CV Thomas, AC Cater, JJ Wheeler. HPCE as an analytical probe for assessing irreversible ligand/macromolecule binding interactions. J Liq Chromatogr 16 1903-1921, 1993. 

Eisen, M. B., Wiley, D. C., Karplus, M., Hubbard, R. E. (1994) HOOK a program for finding novel molecular architectures that satisfy the chemical and steric requirements of a macromolecule binding site. Proteins 19, 199-221. 

Hunston, D.L. (1975) Two techniques for evaluating small molecule-macromolecule binding in complex system. Anal. Biochem., 63, 99-109. 

Consideration of a model in which 1 g of macromolecule binds B grams of water and U3 grams of salt yields = Bi — B3lw3, where the solvent composition is w3 grams of salt per gram of water. In the model example of the macromolecule with associated water and salt molecules, it can be shown that... 

Figure 3. Scattering from silica spheres bound with PEO macromolecules In water (/, compared with free silica spheres (O) and with a concentrated suspension where the spheres repel each other (+). The solvent Is water at pH = 8 In this solvent the spheres bear about 0.3 S10 group per nm of surface, and the macromolecules bind to the remaining SlOH groups (1 ). Very long macromolecules (M 2E6) are used to promote bridging and flocculation with shorter ones no floes are obtained unless the surface charges are neutralized or screened (16).

Metabolites of dimethylaminoazobenzene can bind to liver cell macromolecules. Binding to liver cell macromolecules can then lead to liver carcinomas. Diets high in riboflavin have been shown to reduce the binding of dimethylaminoazobenzene to liver macromolecules. The reduced binding was shown to result in a reduced incidence of liver carcinomas. 

In summary, the extent of passive distribution depends on macromolecule binding in plasma and tissue, lipophilicity, and pKa. The extent of distribution can be evaluated by comparing the apparent volume to the physical volume of body water. Distribution is a kinetic process as reflected by the different terms of volume of distribution V., Vdss, and Vp and their ratios. Vdss is a time-averaged parameter that should be used to compare the extent of distribution among lead optimization candidates. It takes a longer time for a compound with large Vdss to be cleared from the body. 

Many compounds form covalent adducts with solvent molecules. In some cases, the adducts represent the predominant species in solution and/or the species that binds to the macromolecule binding site. Accordingly, accurate prediction of binding affinity is dependent not only on our ability to accurately calculate ligand binding affinities for both the ligand and its solvent adduct, but also on our ability to predict the ratio of the ligand and its adduct in solution. 

Fig. 8.4 (A-N). The excess transverse relaxation rate, A(l/T2), of a halide nucleus in a hypothetical two-site system as a function of the total halide concentration [X ]. Site A represents "free halide ion in solution and site B represents a macromolecule binding site, [m] denotes the concentration of the macromolecule, Vq is the quadrupole coupling constant in the B-site, is the rotational correlation time characterizing the halide in the macromolecular binding site and Kb denotes the binding constant for halide ion to the B-site. The curves have been calculated using Eqs. (8.25) to (8.28) and Eq. (8.40). The results are shown for two different halide exchange mechanisms. Case I represents the "first order" mechanism of Eq. (8.31)...

Figure 11.22 Need of a spacer arm. (A) Ligand without a spacer arm is closely held to the matrix partide. The macrorndlecule cannot attach due to steric hindrance. (B) ligand wUh a spacer arm. Vie macromolecule binds without any steric hindrance.

M. B. Eisen, D. C. Wiley, M. Karplus, and R. E. Hubbard, Proteins Struct., Funct., Genet., 19,199 (1994). HOOK APro am for Finding Novel Molecular Architectures That Satisfy the Chemical and Steric Requirements of a Macromolecule Binding Site. 

A wide variety of techniques have been applied to measure drug-macromolecule binding constants and to characterize drug interactions at the binding site, namely, biochemical binding assays [20], high-performance affinity chromatography, capillary electrophoresis, and fluorescence spectroscopy [21]. 

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