Inhibitors binding

Enzyme Inhibition. En2yme inhibitors (qv) are reagents that bind to the enzyme and cause a decrease in the reaction rate. Irreversible inhibitors bind to the enzyme by an irreversible reaction, and consequendy cannot dissociate from the enzyme or be removed by dilution or dialysis. Examples of irreversible inhibitors are nerve gases such as diisopropylphosphoduoridate [55-91-4] (DEP). 

Slow-binding inhibitors operate by one of two mechanisms. Either the inhibitor binds slowly in an initial step, or the initial binding step occurs quickly, followed by a slow rearrangement of the E-I complex. 

The binding site is located at the tip of the subunit within the jelly roll structure (Figure 5.23). The sialic acid moiety of the hemagglutinin inhibitors binds in the center of a broad pocket on the surface of the barrel (Figure 5.24). In addition to this groove there is a hydrophobic channel that can accomodate large hydrophobic substituents at the C2 position of sialic acid (Figures 5.22 and 5.24). 

Figure 5.24 Space-filling model (green) of the sialic acid binding domain of hemagglutinin with a bound inhibitor (red) Illustrating the different binding grooves. The sialic acid moiety of the Inhibitor binds in the central groove. A large hydrophobic substituent, Ri, at the Cz position of sialic acid binds in a hydrophobic channel that runs from the central groove to the bottom of the domain. (Adapted from S.J. Watowich et al.. Structure 2 719-731, 1994.)...

Figure 11.9 A diagram of the active site of chymotrypsin with a bound inhibitor, Ac-Pro-Ala-Pro-Tyr-COOH. The diagram illustrates how this inhibitor binds in relation to the catalytic triad, the strbstrate specificity pocket, the oxyanion hole and the nonspecific substrate binding region. The Inhibitor is ted. Hydrogen bonds between Inhibitor and enzyme are striped. (Adapted from M.N.G. James et al., /. Mol. Biol. 144 43-88, 1980.)...

FIGURE 7.3 Diversity of structures that interact with the (a) HIV reverse transcriptase inhibitor binding site [8] and (b) the CCR5 receptor mediating HIV-1 fusion [9],... 

The most extensive development of pharmacological inhibitors of MAPK cascades members has been for p38 (Table 1) [3]. Small-molecule inhibitors have been developed for two p38 isoforms (a and (3). Pyridinyl imidazole compounds have been known to block inflammation since the early 1970s. Structural analyses have revealed that p38 kinase inhibitors binds to the ATP-binding pocket of p38 thereby acting as competitive inhibitors. The p38 kinase inhibitor SB202190 is able to bind both the low-activity nonphosphorylated... 

Reversible metabolic inhibition caused by an inhibitor binding to an enzyme site different from the substrate. The degree of inhibition is independent of the substrate concentration. 

Love RA, Parge HE, Yu X, Hickey MJ, Diehl W, Gao J, Wriggers H, Ekker A, Wang L, Thomson JA, Dragovich PS, Fuhrman SA (2003) Crystallographic identification of a noncompetitive inhibitor binding site on the hepatitis C vims NS5B RNA polymerase enzyme. J Virol 77 7575-7581... 

Fig. 7 The influenza virus A sialidase active site showing the five potential inhibitor binding subsites (with S5 containing the hydrophobic pocket formed by reorientation of the Glu276 side-chain), with oseltamivir carboxylate 18 placed in the active site...

Smith BJ, Colman PM, von Itzstein M, Danylec B, Varghese JN (2001) Analysis of inhibitor binding in influenza virus neuraminidase. Protein Sci 10 689-696... 

Suhre WM, Ekins S, Chang C, Swaan PW and Wright SH. Molecular determinants of substrate/inhibitor binding to the human and rabbit renal organic cation transporters hOCT2 and rbOCT2. Mol Pharmacol 2005 67 1067-77. 

Inhibitors are species that bind to enzymes, modifying their activity. Competitive inhibitors bind at the same site as the substrate binds this is analogous to competitive adsorption in heterogeneous catalysis. The reaction scheme becomes ... 

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