Thrombin inhibitors molecular modeling

Hadjipavlou-Litina D (2006) QSAR and Molecular Modeling Studies of Factor Xa and Thrombin Inhibitors. 4 1-53... 

Iwanowicz EJ, Lau WF, Lin J, Roberts DGM, Seiler SM. Retro-binding tripeptide thrombin active inhibitors discovery, synthesis and molecular modeling. J Med Chem 1994 37 2122-2124. 

Peptide chimeras of this type have proven extremely valuable for the examination of an array of recognition events. In conjunction with molecular modeling, peptidomimetic substrates and inhibitors of human thrombin were designed and synthesized to evaluate our proposed structure for the thrombin-bound conformation of fibrinopeptide A (Scheme 2i)J%]... 

D-QSAR and Molecular Modeling Studies on Thrombin Inhibitors... 

Despite the ubiquitous nature of serine proteases, it is possible to design specific thrombin inhibitors by taking advantage of the accessory regulatory binding sites on the enzyme surface. The inibitors are efficacious in several experimental models of thrombosis, and above all, illustrate the feasibility of low molecular weight protein mimetics. 

The authors used the information gleaned from these studies to design the closely related chloromethyl ketone inhibitor of thrombin FPAM (68). Molecular modeling of this proposed inhibitor docked in the thrombin active site indicated that interactions similar to those important to fibrinopeptide binding could be obtained. Subsequent X-ray crystal structure analysis of the 68-thrombin complex was supportive of the peptidomimetic hypothesis,... 

The general drawback of the Wessler model is the static nature of the venous thrombus development. To overcome this problem some investigators have developed more dynamic models with reperfusion of the occluded vessel segments after clot development. Depending on the time of test compound administration (pre- or post-thrombus initiation), the effect on thrombus growth and fibrinolysis can be evaluated. Levi et al. (1992) have used this model to assess the effects of a murine monoclonal anti-human PAI-1 antibody and Biemond et al. (1996) compared the effect of thrombin and factor Xa inhibitors with a low molecular weight heparin. 

Molecular replacement. When a suitable model of the unknown crystal structure is available, it can be used to solve the phase problem. Examples are the use of the structure of human thrombin to solve the structure of bovine thrombin, the use of a known antibody fragment to solve the sttucture of an unknown antibody, or the use of the stmcture of an enzyme to solve the structure of an inhibitor complex in a different crystal form. The model is oriented and positioned in the unit cell of the unknown crystal with the use of rotation and translation functions, and the oriented model is subsequently used to calculate phases and an electron density map. 

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