Thrombin-inhibitor complexes

Obst U, Gramlich V, Diederich F, Weber L, Banner DW. Design of novel, nonpeptidic thrombin inhibitors and structure of a thrombin-inhibitor complex. Angew Chem Int Ed Engl 1995 34 1739. 

Protease 3D structural models thrombin-inhibitor complex and drug design... 

Chow MM, Edgar F, Meyer J, Bode W, Kam C-M, Radhakrishnan R, Vijayalakshmi J, Powers JC (1990) The 2.2-A resolution X-ray crystal structure of the complex of trypsin inhibited by 4-chloro-3-ethoxy-7-guanidinoisocoumarin a proposed model of the thrombin-inhibitor complex. J Am Chem Soc 112 7183-7189... 

Recognition at the Thrombin Active Site Structure-Based Design and Synthesis of Potent and Selective Thrombin Inhibitors and the X-Ray Crystal Structures of Two Thrombin-Inhibitor Complexes. 

Correlation of Binding Affinities With Non-Bonded Interaction Energies of Thrombin-Inhibitor Complexes. 

Solvent or water molecules can be recruited by inhibitors to enable them to bind better. For example, the early thrombin-inhibitor complexes MD-805 and PPACK have water strongly bound to the guanidine group in the recognihon pocket, in MD-805 it makes a bridge to the inhibitor carboxylate, while in PPACK it makes a bridge to the inhibitor N-terminal -NH3. 

In Section 7.7, the binding modes revealed by some crystal structures of thrombin-inhibitor complexes were discussed. Inhibitor studies on thrombin have been... 

It is now possible to produce a high-resolution structure of a thrombin-inhibitor complex in a day or so, which is quicker and easier than chiral separation. Where selectivity against related enzymes is an issue, which it certainly is for fhrombin, it has been repeatedly found that this can only be understood, and fhus improved, if the binding modes to these other enzymes can also be determined. This is particularly true where diastereomers are involved. 

Grootenhuis PDJ, vanGalen PJM. Correlation of binding affinities with non-bonded interaction energies of thrombin-inhibitor complexes. Acta Cryst 1995 D5L560-566. 

P. D. J. Grootenhuis and P. J. M. Van Galen, Acta Crystallogr., D51,560 (1995). Correlation of Binding Affinities with Nonbonded Interaction Energies of Thrombin-Inhibitor Complexes. 

D, H W Hoeffken, D Crosse, J Stuerzebecher, P D Martin, B F P Edwards and W Bode 1992. Refined 2.3 Angstroms X-Ray Crystal Structure of Bovine Thrombin Complexes Formed witli he 3 Benzamidine and Arginine-Based Thrombin Inhibitors NAPAP, 4-TAPAP and MQPA A Starting Point for Improving Antithrombotics. Journal of Molecular Biology 226 1085-1099. 

Four naturally occurring thrombin inhibitors exist in normal plasma. The most important is antithrombin III (often called simply antithrombin), which contributes approximately 75% of the antithrombin activity. Antithrombin III can also inhibit the activities of factors IXa, Xa, XIa, Xlla, and Vila complexed with tissue factor. a2-Macroglobulin contributes most of the remainder of the antithrombin activity, with heparin cofactor II and aj-antitrypsin acting as minor inhibitors under physiologic conditions. 

Zwitterionic character is notable in several therapeutic area series, e.g. in angiotensin-converhng enzyme inhibitors, quinolone anhbacterials and thrombin inhibitors. The aqueous solubiUty measurement of zwitterions is very pH dependent as might be expected. The relationship of aqueous solubiUty to ionization state is extraordinarily complex if the zwitterion is of the type capable of an equi-Ubrium between true zwitterion and formally neutral forms (e.g. as in a quinolone antibacterial). For these types of complex equilibria, salt effects on solubility may be unexpectedly large, e.g. solubility unexpectedly may track with the chaotropic character of the salt... 

Although the fibrinolytic pathway is activated when thrombin binds to thrombomodulin, the thrombin-thrombomodulin complex, in addition to activating protein C (APC), activates a fibrinolysis inhibitor called the thrombin-activatable fibrinolysis inhibitor (TAFIa). Thus plasmin generation and, in turn, fibrinolysis are... 

Schematic representation of Subsite Utilization in Thrombin Complexes (after Reference 8). Fibrinogen interacts with three thrombin subsites (here thrombin is represented by a large oval and the interconnected subsites by an irregular three-armed shape). Physiological effectors of thrombin and thrombin inhibitors form distinct interactions at these subsites. Additional subsites, such as the heparin-binding site, exist on the thrombin surface and are not indicated here.

Discovery of therapeutically effective thrombin inhibitors involves issues such as affinity and selectivity, bioavailability, and formulation. In addition to these relatively common concerns, the complex in vivo mechanisms designed to... 

Wu T-P, Yee V, Tulinsky A, Chrusciel R, Nakanishi H, Shen R, Priebe C, Kahn M. The structure of a designed peptidomimetic inhibitor complex of oc-thrombin. Protein Engineering 1993 5 471-478. 

Since, to date, it has not been possible to directly obtain x-ray structures of inhibitor complexes with Factor Xa, the substantial information available with respect to how serine proteases, particularly thrombin, bind inhibitors can... 

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