Inhibitors ideal

The second-generation antidepressants, particularly RIMAs and SSRJs, are much less toxic ia overdose than the older TCAs and irreversible MAO inhibitors. However, similar to first-generation antidepressants, the therapeutic effect only becomes manifest after several weeks. Up to one-third of depressed patients are nonresponders. Ideally, an antidepressant would combine a more rapid onset of action with greater clinical efficacy and a higher responder rate, as well as even better tolerability. 

Inhibitors are often iacluded ia formulations to iacrease the pot life and cute temperature so that coatings or mol dings can be convenientiy prepared. An ideal sUicone addition cure may combine iastant cure at elevated temperature with infinite pot life at ambient conditions. Unfortunately, real systems always deviate from this ideal situation. A proposed mechanism for inhibitor (I) function is an equUibtium involving the inhibitor, catalyst ligands (L), the sUicone—hydride groups, and the sUicone vinyl groups (177). 

Ideally, a system for recycling spent antifreeze consists first of the removal of the deleterious contaminants such as the corrosion products, corrosive ions, degradation products, and remaining inhibitors. Then the clean fluid could be reinhibited to a known concentration of both inhibitors and glycol. 

Water-borne primers may or may not contain chromate-based corrosion inhibitors. The limited solubility of chromate salts in water makes them less than ideal for use in water-based primers, and much work has gone into developing alternatives [36], but the performance of recently developed water based primers using strontium chromate as the corrosion inhibitor is excellent, however, and appears equivalent to the solvent-borne analogues [37]. 

Candidate protease inhibitor drugs must be relatively specific for the HIV-1 protease. Many other aspartic proteases exist in the human body and are essential to a variety of body functions, including digestion of food and processing of hormones. An ideal drug thus must strongly inhibit the HIV-1 protease, must be delivered effectively to the lymphocytes where the protease must be blocked, and should not adversely affect the activities of the essential human aspartic proteases. 

Inhibitors or retarders that give inert products are called ideal .173 The term ideal inhibitor has also been used to describe a species that stops all polymerization until such time as it is completely consumed (i.e. the induction period) and then allows polymerization to proceed at the normal rate. However, in many cases the products formed during inhibition or retardation are not inert. Four... 

The effectiveness of inhibitors is measured in terms of the rate constant ratio kz/kp and the stoichiometric coefficient. The stoichiometric coefficient is the moles of radicals consumed per mole of inhibitor. These parameters may be determined by various methods. A brief description of the classical kinetic treatment for evaluating k7/kp follows. Consider the reaction scheme shown which describes ideal inhibition and retardation (Scheme 5.11). 

The kinetics and mechanism of inhibition by stable radicals has been reviewed by Rozantsev el al,lS3 Ideally, for radicals to be useful inhibitors in radical polymerization they should have the following characteristics ... 

In all space heating boiler systems there is a tendency to keep water treatment programs as simple as possible. Ideally, chemical inhibitors should be added in proportion to MU demands, metered water consumption, oxygen content, or other preemptive measurement. More typically, the standard process is to periodically (weekly to monthly) analyze the BW for a few basic control parameters, including measuring the multimetal corrosion inhibitor reserve, and then to merely top-up the inhibitor when the reserve is below the minimum specification. Chemical treatment often is added directly to the BW by hand-pump via a hose cock (bib cock) connection. 

It is important to emphasize that this lattice database is highly idealized compared to real databases. Unlike the lattice database, real databases cannot be treated as thermodynamic ensembles of protein-ligand complexes equilibrated at room temperature [33,34]. Two of the more straightforward reasons are mentioned here. First, real databases are inherently biased toward strong binders (K < 10 pM), because weak binders are difficult to crystallize and of lesser interest. Second, as mentioned above, real databases are not composed of a representative selection of proteins and ligands, and their compositions are biased toward peptide and peptidomimetic inhibitors and certain protein superfamilies. In contrast, because only one protein and four ligand types are used, the lattice database should have representative ligand compositions. 

In an ideal pure preparation of Na,K-ATPase from outer renal medulla, the al subunit forms 65 70% of the total protein and the molar ratio of a to is 1 1, corresponding to a mass ratio of about 3 1 [1,5]. Functionally the preparation should be fully active in the sense that each a/ unit binds ATP, Pj, cations and the inhibitors vanadate and ouabain. The molecular activity should be close to a maximum value of 7 000-8 000 Pj/min. The highest reported binding capacities for ATP and phosphate are in the range 5-6 nmol/mg protein and close to one ligand per otjS unit [29], when fractions with maximum specific activities of Na,K-ATPase [40 50 pmo Pj/min mg protein) are selected for assay. 

It is a rarity that the first ligand to be designed is the final one. Thus, it is common to go through the structure-based design cycle (Fig. 2) several times with each class of inhibitors being designed. This iteration should continue until the ideal molecule that will be advanced to development has been identified. 

The structures of enzyme active sites, and other ligand binding pockets on enzymes, are ideally suited for high-affinity interactions with drug-like inhibitors. 

Figure 3.14 Idealized van t Hoff plot of the temperature dependence of the affinity of a peptide inhibitor for die enzyme hdm2.

To account for differences in the Hill coefficient, enzyme inhibition data are best ht to Equation (5.4) or (5.5). In measuring the concentration-response function for small molecule inhibitors of most target enzymes, one will hnd that the majority of compounds display Hill coefficient close to unity. However, it is not uncommon to hnd examples of individual compounds for which the Hill coefficient is signihcandy greater than or less than unity. When this occurs, the cause of the deviation from expected behavior is often reflective of non-ideal behavior of the compound, rather than a true reflection of some fundamental mechanism of enzyme-inhibitor interactions. Some common causes for such behavior are presented below. 

Figure 5.7 Comparison of four-parameter fy-maxi mum, v-minimum. IC50, and h) and two-parameter (IC50 and h) fits of non-ideal concentration-response data. In panels A and B the data indicate a nonzero plateau at low inhibitor concentration that might reflect a low-amplitude, high-affinity second binding interaction. In panels C and D the data indicate a plateau at high inhibitor concentration that does not achieve full inhibition of the enzyme. There could be multiple causes of behavior such as that seen in panels C and D. One common cause is low compound solubility at the higher concentrations used to construct the concentration-response plot. Note that the discordance between the experimental data and the expected behavior is most immediately apparent in the plots that are fitted by the two-parameter equation.

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