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International
Tables for Crystallography Volume F Crystallography of biological macromolecules Edited by M. G. Rossmann and E. Arnold © International Union of Crystallography 2006 |
International Tables for Crystallography (2006). Vol. F. ch. 1.3, p. 21
Section 1.3.4.3.4. Cardiovascular disorders
aBiomolecular Structure Center, Department of Biological Structure, Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195-7742, USA |
Thrombosis is a major cause of morbidity and mortality, especially in the industrial world. Hence, major effort is expended by pharmaceutical industries in the development of new classes of anti-coagulants with fewer side effects than available drugs, such as heparins and coumarins. Because blood coagulation is the result of an amplification cascade of enzymatic reactions, many potential targets are available. At present most of the effort is directed towards thrombin (Weber & Czarniecki, 1997![[link]](/graphics/greenarr.gif)
) and factor Xa (Ripka, 1997), responsible for the penultimate step and the step immediately preceding it in the cascade, respectively. Thrombin is especially fascinating owing to the presence of at least three subsites: a primary specificity pocket with the catalytic serine-protease machinery, an exosite for recognizing extended fibrinogen and an additional pocket for binding heparin. This knowledge has led to the design of bivalent inhibitors which occupy two sites with ultra-high affinity and exquisite specificity. Several of these agents are in clinical trials (Pineo & Hull, 1999).
References
Pineo, G. F. & Hull, R. D. (1999). Thrombin inhibitors as anticoagulant agents. Curr. Opin. Hematol. 6, 298–303.Google Scholar
Ripka, W. C. (1997). Design of antithrombotic agents directed at factor Xa. In Structure-based drug design, edited by P. Veerapandian, pp. 265–294. New York: Marcel Dekker. Google Scholar
Weber, P. C. & Czarniecki, M. (1997). Structure-based design of thrombin inhibitors. In Structure-based drug design, edited by P. Veerapandian, pp. 247–264. New York: Marcel Dekker.Google Scholar
