Relative inhibitor affinity

Figure 6. A hypothetical scheme for the control of the number of active crossbridges in smooth muscle. Following the activation of a smooth muscle by an agonist, the concentrations of intermediates along the main route begins to build up transiently. This is shown by the thickened arrows. Also, cAMP is generated which is universally an inhibitor in smooth muscle. Cyclic AMP in turn combines with protein kinase A, which accounts for most of its action. The downstream mechanisms, however, are not well worked out and at least three possibilities are likely in different circumstances. First, protein kinase A is known to catalyze the phosphorylation of MLCK, once phosphorylated MLCK has a relatively lower affinity for Ca-calmodulin so that for a given concentration of Ca-calmodulin, the activation downstream is reduced. The law of mass action predicts that this inhibition should be reversed at high calcium concentrations. Other cAMP inhibitory mechanisms for which there is evidence include interference with the SR Ca storage system, and activation of a MLC phosphatase.

Characterization of inhibition modality, and from this quantitative determination of enzyme-inhibitor dissociation constants, constitutes the only rational, quantitative means of assessing relative compound affinity for a target enzyme. 

It is often the case that alchemical transformations are used to compare the binding affinity of two ligands and Jz 2 to a receptor molecule R. For example Jz i and -S 2 might be two putative inhibitors of an enzyme R. If AA (respectively, AA2) is the free energy of binding (respectively, Jz 2) to R, we can define the relative binding affinity by AAA = AA2 — AA4. 

Swaan, P. W., Stenhouwer, M. C., Tukker, J., Molecular mechanism for the relative binding affinity to the intestinal peptide carrier. Comparison of three ACE-inhibitors enalapril, enalaprilat, and lisinopril, Biochim. Biophys. Acta 1995, 3236, 31-38. 

Although, it is well known that not every inhibitor is a substrate, it is generally believed that every substrate should show inhibitory effects on other substrates. However, many substrates show a relatively low affinity for the protein and do not... 

P. W. Swaan, M. C. Stehouwer, J. J. Tukker, Molecular Mechanism for the Relative Binding Affinity to the Intestinal Peptide Carrier. Comparison of Three ACE-Inhibitors Enalapril, Enalaprilat and Lisinopril , Biochim. Biophys. Acta 1995, 1236, 31-38. 

An amidrazone (58) derived from 5-amino-5-deoxy-L-fuconolactam was found to inhibit a recombinant human a-L-fucosidase with a K -value of 820 nmol/1 [ 111 ]. A simple synthesis of 1,5-dideoxy-1,5-imino-D-arabinitol (59), previously prepared by Ganem et al. [49] as a potential maimosidase inhibitor, was applied to the affinity purification of a-L-fucosidase from bovine kidney by an improved method and the characterization of the enzyme thus obtained [112]. The relatively low affinity of this compound to the enzyme (Kj 2.2 pmol/1 at pH 7) compared to 1-deoxyfuconoJirimycin (51) turned out to be advantageous in terms of enzyme recovery and yield. Structurally related, suitably protected 5-amino-5-deoxy-D-arabinopyranose (60), was coupled with a N-acetyl-6-deoxy-6-thio-D-glucosaminide (61) to give a stable thioglycoside (62) [113]. 

Of the clinically tested new antipsychotics, ziprasidone has the highest 5-HT2A/D2 receptor-affinity ratio. Ziprasidone is an antagonist at the a -adrenoreceptor, but its affinity is half that of its D 2 affinity. In addition, compared with its affinity for D 2 and 5-HT2A receptors, ziprasidone has a relatively low affinity for histamine receptors (pKJ = 7.33). In vitro, ziprasidone is a moderately potent inhibitor of neuronal reuptake of norepinephrine, serotonin, and, to a lesser extent, dopamine. This property is shared with some antidepressants, and contrasts with risperidone, which is inactive at all three monoamine uptake sites. 

Lindskog reported that Cl- is a competitive inhibitor of the CO2-HCO3 exchange reaction for isoenzyme I (157c). H NMR experiments (142,157c) and pH dependence of the SCN- inhibition of the 4-nitrophenyl acetate esterase activity have shown that the affinity constants of SCN- for various free enzyme forms follow the order HEH > EH > HE > E (142). The estimated values of the affinity constants are found to be 5x 104 M-1 and < 2 for HEH and E, respectively. Under inhibitory conditions the CA has a finite residual activity (kcai value) which is large for I-, intermediate for N3 and SCN-, and very small for NCO-. This has been explained on the basis of the relative binding affinities of these anions for the enzyme (190). 

Chem., 39, 705 (1996). An Approach to Rapid Estimation of Relative Binding Affinities of Enzyme Inhibitors Application to Peptidomimetic Inhibitors of the Human Immunodeficiency Virus Type 1 Protease. 

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