Hypothetical binding sites

Figure 5.7 Only one of the two amino acid enantiomers shown can achieve three-point binding with the hypothetical binding site (e.g., in an enzyme). 

Hydroxamic acids have been extensively investigated at Abbott, where a hypothetical binding site hypothesis was based on examination of many simple Gj-aralkylhydroxamic acids [294]. Several series of conjugated hydroxamic acids were explored based on this hypothesis, yielding potent 5-LO inhibitors (0.02-2 //M) exemplified by (116)-(119). The most potent of these (119) also inhibited purified porcine leukocyte 5-LO (0.5 //M) [202]. As other workers have found, A-methylation was beneficial for potency. Activity was also seen in a rat peritoneal anaphylaxis model following i.p. (0.2 mg/kg), but not oral, dosing [47]. 

Figure 3.27. (a)Pharmacophore hypothesis with correspondence of functional groups in drugs, A = A, B = B, C = C. (b) Binding-site hypothesis use of drugs with hypothetical binding sites attached (X, Y, and Z overlap). 

Gupta et al. [72] performed an extensive structure-activity comparison regarding cross-resistance in two emetine-resistant CHO cell variants. This study showed that phenanthroindolizidine alkaloids, phenanthroquinolizidine alkaloids, and emetine-related benzoquinolizidines may have the same site of action. The conformation of emetine was suggested to have a close spatial relationship to the other three compound classes, and thus, they could bind to the same hypothetical binding site, Fig. (7). 

If our hypothesis is correct, this hypothetical binding site should also accommodate fluridone, norflurazon and difunone and some possible binding orientations of these molecules are compared with furanone 13 in Figures 7-9. Note that we have attempted to depict the molecules in such a way that key structural features, e.g., the CF3 phenyl and vinylogous amide subunits, occupy the same positions as nearly as possible. Finally, it should be emphasized that considerable further work is required to demonstrate that the furanones actually inhibit phytoene desaturase and to further probe the possibility of a common binding site for the proven inhibitors including those such as fluorochloridone (10) and the m-phenoxybenzamides (4), which do not incorporate the vinylogous amide substructure. 

Fig. (25). Hypothetical binding site model for GABA-antagonistic insecticides established by Ozoe et al, reproduced with permission from the author [165). The picture (bottom) showing picrotoxinin was added by the author of the present publication. Note that PIC was originally assumed to bind in an opposite mode, i.e. the epoxy group was assigned subate A and the lactone structure subsite B. The picture presented here corresponds to the binding mode assumed on grounds of the current knowledge [163,182).

Fig. 8. Hypothetical binding sites between (a) GAj and the dwarf pea receptor (b) GA, and the cucumber receptor . I=obligatory binding sites II=anciUary binding sites III=hydrophobic interaction site IV electrostatic interaction site. (Reprinted with permission from Serebryakov et al.. Phytochemistry 23, 1847 1984. Copyright 1984 Pergamon Press Ltd.)...

Figure 1 A hypothetical binding site model for chloramphenicol analogs. Note that the dichloroacetyl group is postulated to interact with a positively charged gua-nidinium group of the protein and the nitrophenyl group with the it cloud of an uncharged imidazole.

Proline 195 was suggested by Gangola and Shamoo [210] as a component of the hypothetical Ca binding site. Mutation of Pro 195 to alanine and the mutation of several acidic residues in the same area [129] had no effect on the Ca transport, making this proposition also unlikely. 

Figure 4.2 Hypothetical plasma membrane (PM)-associated structure of FR02. Four histidine residues (white spots) predicted to coordinate two intramembraneous haem groups (white bars) are indicated, as are the tetrapeptide binding sites for FAD and N AD(P)H. The sites of mutations in the FRO gene are indicated (frdl-l,frdl-3) i, inside cell o, outside cell. Reprinted with permission from Nature (Robinson et al., 1999). Copyright (1999) Macmillan Magazines Limited.

For all the above reasons we have defined g(C) without reference to any hypothetical, independent-site system. One simply extracts both 1(C) and all from the experimental data, and then constructs the quantity g(C). When the sites are identical in a weak sense, i.e., all k = k, some of the correlations for a given / might differ. For example, four identical subunits arranged in a square will have only one intrinsic binding constant k, but two different pair correlation functions. For this particular example we have four nearest-neighbor pair correlations g (2), and two second-nearest-neighbor pair correlations gJJ)- The average correlation for this case is... 

Figure 6.6 Hypothetical comparison of ambient analyte and mass-sensing analysis of thyroid-stimulating hormone. Solid line indicates mass assay dashed line indicates ambient analyte assay. Antibody affinity of 10"i° liter per mole and volume of 100 pL are assumed. Mass assay assumes 10i° binding sites per 100 pL. (From Silzel, J.W. et al., Clin. Chem., 44, 2036-2043, 1998. With permission.)...

Fig. 3. Ligand binding behavior of a hypothetical protein exhibiting a unit Hill coefficient of (hh = 1). Such behavior would be expected (a) for the case of a protein with only a single binding site or (b) for the case of an oligomeric protein containing n independent and noninteracting binding sites.

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