Inhibitor of trypsin

Application of the CCM to small sets (n < 6) of enzyme inhibitors revealed correlations between the inhibitory activity and the chirality measure of the inhibitors, calculated by Eq. (26) for the entire structure or for the substructure that interacts with the enzyme (pharmacophore) [41], This was done for arylammonium inhibitors of trypsin, Di-dopamine receptor inhibitors, and organophosphate inhibitors of trypsin, acetylcholine esterase, and butyrylcholine esterase. Because the CCM values are equal for opposite enantiomers, the method had to be applied separately to the two families of enantiomers (R- and S-enantiomers). 

Some of the best investigated anti-nutrients are the enzyme inhibitors present in legumes and other plants. The Bowman-Birk and the Kunitz inhibitors of trypsin and other proteases are among the best characterized. In contrast to the non-specific and widespread influences of tannins and lectins (Carmona, 1996), the Bowman-Birk, Kunitz and other such inhibitors target specific enzymes. Corresponding with this, proteases and other digestive enzymes vary in sensitivity to the different inhibitors. 

Guo et al. [57] used this approach to calculate the binding affinities of different inhibitors of trypsin, shown in Fig. 4.16. They proposed to improve the sampling by adding the following biasing potential ... 

Potll inhibitors inhibit several proteases. For example, serine protease inhibitors isolated from Capsicum annum seeds named PSI-1.1 and PST1.2 are strong inhibitors of trypsin and only one order of magnitude less active on chymotrypsin. PSTl.l also has considerable activity against thrombin, whereas factor Xa is inhibited to a lesser extent by PSI-1.1 and PSTl.2. ... 

Tincture of the dried seed, on agar plate at a concentration of 30 p,L/disc, was inactive on Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. Extract of 10 g plant material in 100 mL ethanol was used b Anticoagulation activity. Serpin BSZx (an inhibitor of trypsin and chemotrypsin) inhibited thrombin, plasma kallikrein, factor Vlla/tissue factor, and factor Xa at heparin-independent association rates. Only factor Xa turned a significant fraction of BSZx over as substrate. Activated protein C and leukocyte elastase were slowly inhibited by BSZx, whereas factor Xlla, urokinase and tissue type plasminogen activator, plasmin and pancreas kallikrein, and elastase were not or only weakly affected. Trypsin from Fusarium was not inhibited, while interaction with subtilisin Carlsberg and Novo was rapid, but most BSZx was cleaved as a substrate L... 

Leupeptin is a slow, tight-binding inhibitor of trypsin. Some peptide aldehydes are potent, reversible inhibitors of cysteine proteases forming hemith-ioacetals with the active site cysteine.1 Similarly, peptide nitriles form thioimidate adducts.h... 

In the preparation of amidine-containing substrates and inhibitors of trypsin, various nitriles have been synthesized as intermediates for these amidines. 15 In order to improve the yields of these nitriles and to preserve the optical activity of the amidines, many dehydrating agents such as POCl3, P2Os, TosCl/pyridine, and polyphosphate ester (PPE) and various dehydrating conditions have been evaluated. 101516 ... 

Gourinath, S., Alam, N., Srinivasan, A., Betzel, Ch., and Singh, T. P. (2000). Structure of the bifunctional inhibitor of trypsin and a-amylase from ragi seeds at 2.2 A resolution. Acta Crystallogr. Sect. D 56, 287-293. 

Parellada, J., and M. Guinea. 1995. Flavonoid inhibitors of trypsin and leucine aminopeptidase A proposed mathematical model for IC50 estimation. J Nat Prod 58 823. 

Reduced nitrogen retention was reported when chicks were fed rye diets (18). Supplementation of those diets with amino acids increased the retention of only the supplemented amino acids and not those contributed by the rye. These observations are compatible with the trypsin inhibitor hypothesis of other researchers (9,10). On the other hand, examination of the differences between endosperm and embryo and trypsin inhibitors of barley, wheat, and rye has revealed that, in contrast to certain trypsin inhibitors from leguminous seeds, those from the cereal grains appeared to be relatively weak, nonstoichiometric inhibitors of trypsin (19). 

There is evidence that protein structures are also responsible for cell cohesion in nonpalmo-plantar stratum corneum. When punch biopsies of normal human gluteal skin were incubated in a buffer containing a mixture of the zwitterionic surfactant /V,/V,-dimethyldodecylamine and the anionic surfactant sodium dodecyl sulfate,11 there was dissociation of cells in the stratum corneum but not in the rest of the epidermis. The cell dissociation took place only in the presence of EDTA and was inhibited by the serine protease inhibitor aprotinin.12 Suzuki et al.13,14 presented evidence that spontaneous cell dissociation in nonpalmo-plantar stratum corneum could be inhibited by a combination of inhibitors of trypsin-like and chymotrypsin-like enzymes. Thus, nonpalmo-plantar stratum corneum contains endogenous proteases that mediate cell dissociation. 

Acid chloride handles on various templates 49-51 were acylated with equimolar mixtures of 19 different appropriately protected amines to prepare non-peptidic polyamide libraries. The three templates possess different types of symmetry and offer varying degrees of 3D spatial diversity. Screening for trypsin inhibition employing a chromogenic assay identified the xanthane analog 52 (K, = 9.4 pM) as a moderately active, but structurally novel, inhibitor of trypsin (see Fig. 7) [37]. 

Compounds effecting a stable intermediate in the course of enzymatic catalysis are a sort of mechanism-based inhibitor. However, in this case, the enzymatic activity lost by the formation of the intermediate can regenerate after a certain period. Compounds of this class are often observed for hydrolytic enzymes. The formation of an acyl enzyme intermediate (EA) is a characteristic feature of the reaction catalyzed by these enzymes, as shown in Eq. (6). Esters of p-guanidinobenzoate (9), which were discussed in Sect. 4.1, behave as transient inhibitors of trypsin due to the formation of a relatively stable acyl enzyme. A similar type of inhibition occurs in the temporary... 

Benzo-heterobicycles, (IV), prepared by Wade (5), (V), and Pinto (6), (VI), respectively, were effective as inhibitors of trypsin-based serine proteases, especially factor Xa, and used in in the treatment of thrombotic disorders. 

Reduction and reoxidation have also been used to follow reactivations of biologically active proteins. It was found that an intermediate form of turkey ovomucoid (Figure 14), before complete oxidation, was actually slightly more active as an inhibitor of trypsin than was either the native protein or the completely reoxidized product. 

The digestion of heated or unheated soybean proteins by various enzymes is schematically compared with the nutritive values in Figure 18. Pattern A is typical of pepsin where, because of low pH of the reaction, the protein does not have to be denatured prior to addition to the reaction. Pattern B is typical of enzymes such as papain, bacterial neutral protease etc. where prior de-naturation of the substrate protein is required but there are no inhibitors of the enzyme present. Pattern C is typical of trypsin where prior heat treatment of the substrate protein is required to destroy inhibitors of trypsin as well as to denature the protein for digestion. The decrease in digestibility with prolonged heating in all three cases is due to modification of the substrate protein as described above. 

Ramos et al. [238] have also used the QM/MM LSCF method [312] to understand the reasons why the pancreatic trypsin inhibitor, PTI, behaves as an inhibitor of trypsin rather than as a substrate. In fact, PTI places a peptidic bond between a lysine and an alanine in the catalytic triad of trypsin with the side chain of the lysine in the binding pocket of the enzyme, exactly as a cleavable peptide would do, and this provokes no reaction between PTI and trypsin. The QM/MM calculations performed show that the geometry adopted by the active site of the enzyme in the complex is such that it prevents the nucleophilic attack of the hydroxyl oxygen on the peptide bond of PTI. 

Diarylamidine derivatives have been investigated as antiproteases in 60 out of 62 compounds, one or both of the amidino-substituted aryl moieties included Indene, benzimidazole, benzofuran, benzo[b] thiophene and several other related nitrogen-containing heterocycles.93 one outstanding Inhibitor of trypsin (Ki 1.7x10 8m) is bis(5-amldino-2-benzlml-dazole)methane (10). These compounds demonstrate that variants of small-... 

A weak inhibitor of trypsin was obtained from a large library of dodeca-peptides synthesized on cotton-carriers following a combined positional scanning and iterative deconvolution strategy (library 12) [383], Rebek s approach to the discovery of trypsin inhibitors was to generate a large library... 

Reaction with a macromolecular inhibitor of trypsin Reaction with a cyclic imidocarbonate derivative of Sephadex... 

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