Trypsin inhibitors molecular modeling

Using this approach, Bizzozero and Zweifel (9) and Bizzozero and Dutler (10) have constructed molecular models of two intermediates (an enzyme-substrate complex and a tetrahedral intermediate) by appropriate modification of the models of stable enzyme-species. The stable enzyme-species used (15, 16) are trypsin-benzamidine complex (TR-B) (17), trypsin-pancreatic trypsin inhibitor complex (TR-PTI) (18, 19) and tosyl-chymotrypsin (Tos-CHT) (20) which are related to enzyme substrate complex, tetrahedral intermediate and acyl-enzyme respectively. 

The absorption-enhancing effects of protease inhibitors on the intestinal absorption of water-soluble compounds in rats was also examined. Some protease inhibitors may have absorption-enhancing activities in addition to their protease inhibitory actions (e.g., NaGC) [43, 44]. Aprotinin, bacitracin, and soybean trypsin inhibitor (STI) were used as protease inhibitors, while phenol red and fluorescein isothiocyanate (FITC)-labeled dextran with an average molecular weight of 4000 Da (FD-4) were selected as poorly absorbable and stable model compounds. Bacitracin enhanced the absorption of phenol red from the rat small and large intestine in the presence of the protease inhibitors, and similar results were noted for the intestinal absorption of FD-4 co-administered with bacitracin. Thus, bacitracin was seen to have not only a proteolytic inhibitory action but also an absorption-enhancing capability. 

Brunne, R.M., Liepinsh, E., Otting, G., Wuthrich, K., and Vangunsteren, WF. (1993) Hydration of proteins a comparison of experimental residence times of water-molecules solvating the bovine pancreatic trypsin-inhibitor with theoretical-model calculations. Journal of Molecular Biology, 231, 1040-1048. 

Wt of polypeptide drug, using insulin, calcitonin, trypsin inhibitor and angiotensin II as model polypeptides. Release rates fix>m these systems were controlled by varying the molecular weight (M. Wt.) of the polymers (19), and insulin was used as a model polypeptide drug. 

Tables 13.5 and 13.6 summarize the results of building 1-SVM models on the basis of continuous molecular fields for HIV reverse transcriptase (HIVRT) and trypsin inhibitors. As follows from Table 13.5, the best performance for HIVRT is obtained by the model constracted using the steric kernel and resulting in an AUC value of 0.75. For this target, the use of a hnear combination of several kernels does not improve the AUC value. At the same time, for trypsin inhibitors, rather high AUC values (0.86-0.91) were obtained on the basis of individual models constructed with the use of all three kernels, which is likely due to their mutual correlation. However, for this target, the use of a linear combination of all kernels increases the AUC value up to 0.94.

In a recent study, Wlodek et al. investigated the extent to which the assumed protonation state of a protein influences its molecular dynamics trajectory. The authors also determined how often their titration algorithm predicted ionization states identical to those imposed on the groups, when applied to a set of structures derived from a molecular dynamics trajectory. As a model they took the bovine pancreatic trypsin inhibitor (BPTI), a 58-residue protein that is often used as the prototypical small protein in many experimental and theoretical studies. 

Finishing this section, I want to mention some work on water in bio-molecular systems in solution. Wierzuchowska and Blicharska studied proton relaxation and CPMG relaxation dispersion for water protons in solutions of some proteins. The dependences on the protein concentration were also obtained. Persson and Halle analysed the millisecond all-atom MD trajectory (produced by Shaw et for the protein bovine pancreatic trypsin inhibitor and compared the results with the experimental NMRD data as interpreted using the exchange-mediated orientational randomization model. I shall return to the issue of water dynamics in biological gels in subsection 3.5.4. 

Quasi-harmonic analysis is the computation of the normal modes of a molecule from atomic displacements generated by a molecular dynamics simulation. In this case, the atomic coordinate fluctuations are inversely related to the force constants, which are the second derivatives of the potential function. This formulation allows anharmonic motions, arising either from continuous diffusive motion or from transitions between wells, to be included implicitly within a harmonic representation, Brooks and co-workers " have carried out a comparison of different approaches to calculating the harmonic and quasiharmonic normal modes for the protein bovine pancreatic trypsin inhibitor (BPTI) with different force field and simulation models, Yet another approach, called essential dynamics, differs from quasi-harmonic analysis in that the atomic masses are not considered and motion is not reduced to a harmonic form, ... 

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