Dependent Inhibition

Multiple classes of compounds are now known that undergo P450-catalyzed activation to reactive intermediates that irreversibly or quasi-irreversibly inactivate the enzyme responsible for their activation. This irreversible inactivation by a catalytically generated species is superimposed on the reversible inhibition associated with competitive binding of the parent agent to the ferric enzyme. Mechanism-based - (catalysis-dependent) inactivators can be highly enzyme-specific because 

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Flurbiprofen and indomethacin, which comprise the third class of inhibitors, cause a slow, time-dependent inhibition of COX-1 and COX-2, apparently via formation of a salt bridge between a carboxylate on the drug and Arg , which lies in the tunnel. 

Also, phosphorylation of Akt results in activation of sterol regulatory-element binding protein 1 (SREBP1), a key transcription factor involved in regulation of lipogenic enzymes. In addition, some of the effects of insulin on cell proliferation and survival may be explained by an Akt-dependent inhibition of apoptosis through phosphorylation and inactivation of proa-poptotic proteins (e.g., BAD, Caspase 9). 

The nicotinic acetylcholine (nACh) receptor also displays sensitivity to inhalants (Bale et al. 2002). To varying degrees, toluene appeared to antagonize the function of nACh receptors that comprise different subunits. At concentrations of 50 pM to 10 mM, toluene produced a reversible, concentration-dependent inhibition of acetylcholine-induced current in Xenopus oocytes expressing various nicotinic receptor subtypes, with the ol — 2 d ct3—P2 subunit combinations being more sensitive to inhibition than other receptor... 

IFN-)il exhibits dose- and time-dependent inhibition of HCV rephcation in various models, independently of type I and IIIFN receptors and induced pathways (Marcello et al. 2006). A pegylated form of IFN-A, will soon enter clinical evaluation. 

Figure 4. Concentration-dependent inhibition of electric eel AChE by ANTX-A(S). AChE and AhTrX-A(S) were incubated for 2 min. before inhibition rate was determined. Key (A) 0.079 ixg/mL ( ) 0.032 xg/mL (V) 0.016 lig/mL >) 0.0032 ig/mL ( ). 0016 tigjmL. NOTE Total inhibition occurs when 0.158 tiglmL ANTX-A(S) is preincubated with AChE for two minutes.

Figure 6. The effects of 2.6 mM 3,3 -dimethylbutyl acetate on the concentration-dependent inhibition of AChE by ANTX-A(S). Conditions and symbols are the same as Figure 5.

The PL-catechin conjugate showed greatly amplified concentration-dependent inhibition activity against bacterial collagenase (ChC) on the basis of the catechin unit, which is considered to be due to effective multivalent interaction between ChC and the catechin unit in the conjugate. The kinetic study suggests that this conjugate is a mixed-type inhibitor for ChC. Hyaluronidase is an enzyme which catalyzes hydrolysis of hyaluronic acid and is often involved in a number... 

Petry, T.W., Wolfgang, G.H., Jolly, R.A., Ochoa, R. and Donarski, W.J. (1992). Antioxidant-dependent inhibition of diquat-induced toxicity in vivo. Toxicology 74, 33-43. 

K. J. (1990). Time-dependent inhibition of oxygen radical induced lung injury. Inflammation 14, 509-522. 

AM1241 (360) exhibited high affinity and selectivity for CB2 [it (CBi) = 280 nM, (CB2) = 3.4 nM]. (360) Dose dependently inhibited experimental neuropathic pain in a spinal nerve ligation-induced tactile and thermal hypersensitivity model [224]. Other indole derivatives bearing sulfonamide moieties on the side chain, such as compound (361), were disclosed [225]. Though 67 derivatives including pyridyl and other heteroaromatics instead of the indole core were listed, no specific biological data were shown. 

If the inhibitor potency is such that the concentration of inhibitor required to affect significant, time-dependent inhibition is similar to the concentration of enzyme, then one must account for the tight binding nature of the inhibition (discussed further in Chapter 7). In this case Equation (6.1) is modified as follows ... 

The KA values reported by Williams et al. can be used to calculate the relative change in free energy for the enzyme-ligand complexes as described in Chapter 3, fixing the AG ng for the free enzyme at zero (Table 6.3). These data allow us to construct an energy level diagram for the process of time-dependent inhibition of... 

Methotrexate is a valuable drug that is commonly used in the treatment of inflammatory diseases, autoimmune diseases, and proliferative dieases. Its true potency can only be realized by the proper, quantitative analysis of the time-dependent inhibition of DHFR by this compound. 

MCF-7 hSMCs Dose-dependent inhibition of cell proliferation No inflammation [90]... 

Sestan, N., Artavanis-Tsakonas, S. and Rakic, P. (1999), Contact-dependent inhibition of cortical neurite growth mediated by Notch signaling , Science, 286, 741-746. 

TBTC1 produced a dose-dependent inhibition of ANP on vascular smooth muscle responses with an effect on norepinephrine, nitroprusside and atrial natriuretic peptide in isolated aortic rings of rats. The inhibition of vasorelaxation was accompanied by a parallel inhibition of ANP-induced cGMP generation29. 

D. H. Rich, and E. T. Sun, Mechanism of inhibition of pepsin by pepstatin. Effect of inhibitor structure on dissociation constant and time-dependent inhibition, Biochem. Pharmacol. 29 2205 (1980). 

McGuinness, T. L., Brady, S. T., Gruner, J. et al. Phosphorylation-dependent inhibition by synapsin I of organelle movement in squid axoplasm. /. Neurosci. 9 4138-4149, 1989. 

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