Ligand trypsin

Trypsin is a major proteolytic digestive enzyme and the identified endogenous ligand for proteinase-activated receptor 2 (PAR 2). 

Irreversible inhibition is probably due to the alkylation of a histidine residue.43 Chymotrypsin is selectively inactivated with no or poor inhibition of human leukocyte elastase (HLE) with a major difference the inactivation of HLE is transient.42,43 The calculated intrinsic reactivity of the coumarin derivatives, using a model of a nucleophilic reaction between the ligand and the methanol-water pair, indicates that the inhibitor potency cannot be explained solely by differences in the reactivity of the lactonic carbonyl group toward the nucleophilic attack 43 Studies on pyridyl esters of 6-(chloromethyl)-2-oxo-2//-1 -benzopyran-3-carboxylic acid (5 and 6, Fig. 11.5) and related structures having various substituents at the 6-position (7, Fig. 11.5) revealed that compounds 5 and 6 are powerful inhibitors of human leukocyte elastase and a-chymotrypsin thrombin is inhibited in some cases whereas trypsin is not inhibited.21... 

Radmer, R J. Kollman, P.A., The application of three approximate free energy calculations methods to structure based ligand design trypsin and its complex with inhibitors., J. Comput. Aided Mol. Des. 1998,12, 215-227... 

One of the most critical technical issues regarding LIE type of calculations seems to be the treatment of electrostatic interactions, at least for charged ligands. These problems were discussed in Ref. 19 using the trypsin-benzamidine complex as an illustration. The starting point was then that one should expect, or require, that the electrostatic free energies calculated with the LIE method have some physical meaning, even in... 

This approach was first applied toward an understanding of discriminating interactions in the serine proteases factor Xa, thrombin and trypsin [108] and provided selectivity information for all important serine protease subpockets, which are in agreement to experimental selectivities of typical protease inhibitors. This approach was complemented by a 3-D-QSAR selectivity analysis on a series of 3-amidinobenzyl-lH-indole-2-carboxamides [107], which points, from the viewpoint of the ligands, to similar main interactions driving selectivity between key enzymes in the blood... 

Reyda, S., Sohn, C., Klebe, G., Rall, K., Ullmann, D., )akubke, H.D., and Stubbs, M.T. Reconstructing the binding site of factor Xa in trypsin reveals ligand-induced stmctural plasticity. J. Mol. Biol. 2003, 325, 963-977. 

Kasai, K., Ishii, S. Quantitative analysis of afSnity chromatography of trypsin. A new technique for investigation of protein-ligand interaction. J Biochem 1975, 77, 261-264. 

Binding of thyinidine-3, 5 -diphosphate (pdTp) and Ca-+ to nuclease induces resistance to proteolysis by a number of proteases (47, 53). Trypsin rapidly cleaves the peptide bond between residues 5 and 6 of the liganded nuclease. The fragment thus formed, nuclease-(6-149), possesses enzymic activity and structure similar to nuclease (48)- Further cleavage of nuclease-(6-149) in the presence of the ligands takes place... 

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