Kinetics of Inhibition

Inhibitors are evaluated by measuring IC50 values, which usually can be estimated by fitting the following equation to dose-response data 

The dose-response equations deployed to analyse most enzyme inhibition data are dependent upon there being a steady state (the degree of inhibition not changing during the assay), approximately equal concentrations of free and total inhibitor, and a one to one stoichiometry for binding and inhibition.29 Active compounds follow a range of kinetic mechanisms, which may be classified in various ways, for example according to dependence upon ATP or reversibility. Below, I describe some of the most common mechanisms. 

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It is clear that many procedures used to evaluate chain transfer constants can also be used to evaluate the kinetics of inhibition. The following sections will show that the mechanism for inhibition is often more complex than suggested by Scheme 5.11. 

More recent detailed kinetic investigations have revealed that actinonin is a time-dependent, essentially irreversible, inhibitor of PDF enzymatic activity [72]. This study demonstrated that the kinetics of inhibition of... 

Table 6.2 Summary of the kinetics of inhibition of MMP2 and MMP9 by compounds 1 and 2 of Bernardo et al. (2002)...

Amor, L., Kennes, C., and Veiga, M., Kinetics of inhibition in the biodegradation of monoaromatic hydrocarbons in presence of heavy metals, Bioresour Technol, 78 (2), 181-185, 2001. 

This greatly alters the kinetics of inhibited oxidation by making it dependent on p02, since chain termination by reaction (16) competes with reaction (1) of chain propagation. The rate of oxidation becomes dependent on the dioxygen partial pressure. If the radical formed in the reaction of an acceptor with the alkyl radical does not participate in chain propagation, the following equations are valid for description of t, v, and A[02] ... 

Quasistationary Kinetics of Inhibited Autoxidation Topological Kinetics of Inhibited Oxidation of Hydrocarbons... 

I. Kende and M. Azori Kinetics of inhibition of styrene polymerization by nitro compounds. IUPAC Symposium on Macromolecular Chemistry, Moscow 1960, Section II 31. 

Although the kinetics of inhibition of xenobiotic-metabolizing enzymes can be investigated in the same ways as any other enzyme mechanism, a number of problems arise that may decrease the value of this type of investigation. They include the following ... 

Figure 6. Kinetics of inhibition of barley ALS by triazolopyrimidine varied substrate — pyruvate.

In a number of cases equation (13) has been found satisfactorily to describe the kinetics of inhibition of micellar catalysis (Bunton et al., 1968) however the assumptions made in this treatment obviously represent over-simplifications and are invalid in a variety of instances (Bunton et al., 1968 Bunton and Robinson, 1968, 1969b). 

Famin, O. Krugliak, M. Ginsburg, H. Kinetics of inhibition of glutathione-mediated degradation of ferriprotoporphyrin IX by antimalarial drugs. Biochem. Pharmacol, 1999, 58(1) 59-68. 

So-called ideal first-order kinetics of inhibition are obtained under the commonly observed conditions when the concentration of the Michaelis-type complex is small, 2 is high, k-t, is much smaller than 2, and [OP] > 10[E-OH], where [E-OH] = concentration of native enzyme. In such cases,... 

Stojiljkovic, M.P., Pantelic, D., Maksimovic, M. (2001). Tabun, sarin, soman and VX poisoning in rats kinetics of inhibition of central and peripheral acetylcholinesterase, ageing, spontaneous and oxime-facilitated reactivation. Vll International Symposium on Protection against Chemical and Biological Agents. Stockholm, Sweden, June 15-19,... 

Molecules present in the feed inhibit some reactions catalyzed by enzymes. In this problem, the kinetics of inhibition are investigated (from M. L. Shuler and F. Kargi, Bioprocess Engineering, Basic Concepts, Prentice Hall, Englewood Cliffs, NJ, 1992). 

Dunfield P. and Knowles R. (1995) Kinetics of inhibition of methane oxidation by nitrate, nitrite, and ammonium in a Humisol. Appl. Environ. Microbiol. 61, 3129-3135. 

Factor Xa inhibitors vary in their efficacy to inhibit factor Xa depending on molecular size, access to clot bound fector Xa, access to prothrombinase bound factor Xa, specificity and kinetics of inhibition. It is probably the inhibition of clot bound fector Xa that relates to the prolongation of the aPTT as observed with some of the fector Xa inhibitors and, therefore, the inability to inhibit clot bound factor Xa that relates to a lack of aPTT prolongation by other agents. DX-9065a with a relatively lower molecular weight may be more effective in the inhibition of clot bound fector Xa than TAP or pentasaccharide. 

Cyclopropanone hydrate has been reported to be a potent but reversible inhibitor of a number of enzymes which are sensitive to thiol reagents The kinetics of inhibition... 

Metformin profoundly alters the sensitivity of adenylate cyclase to inhibition by insulin, with inhibition being increased to some 32% using liver membranes from either lean or obese animals (Gawler et al., 1988, 1989). Metformin also changes the kinetics of inhibition of adenylate cyclase by insulin (Gawler et al., 1988). 

Balzarini, J., Perez-Perez, M.-J., San-F61ix, A., Camarasa, M.-J., Bathurst, I. C., Barr, P. J., and De Clercq, E. (1992) Kinetics of inhibition of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase by the novel HIV-1-specific nucleoside analogue l-[2, 5 -bis-0-(tert-butyldimethylsilyl)-p-D-ribofuranosyl]-3,-spiro-5"-[4"-amino-l",2"-oxathiole-2",2"-dioxide]-thymine (TSAO-T)../. Biol. Chem. 267, 11,831-11,838. 

Graham, P.S., Hcllyer, R.O. and Ryan, A.J, (1970). The kinetics of inhibition of drug metabolism in vitro bv some natural l v occurring compounds. Iliac hem. Pharmacol. 19, 769-775. 

No data on the inhibitory action of many of the chelating agents known to combine with zinc (Martell and Calvin, 1952 James, 1953) have been published. Similarly, there is little information on the kinetics of inhibition with the agents referred to above. Pending such data, therefore, their action on zinc can only be inferred, justifiable though this interpretation may be. 

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