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IX. Conclusions
Page 289
Factor Xa is clearly an important component of the coagulation process and inhibition of this enzyme
can lead to potent anticoagulant effects. Recently, a number of naturally occurring anti-Factor-Xa
polypeptides have been isolated from several hematophagous organisms including ticks, leeches, and
hook- worms. With the exception of TAP, these molecules appear to bind to Factor Xa by the standard
mechanism of inhibition proposed earlier [49]. The sequence information derived from these inhibitors
as well as the natural cleavage sites of substrates of Factor Xa can be used along with the conformational
constraints imposed by the proposed substrate-like binding to define the pharmacophore requirements of
the active site of Factor Xa. The structurally rigid BPTI mutants, which have been found to be potent
Factor Xa inhibitors, also provide important conformational information particularly with regard to the
specific binding interactions on the P' side of the Factor Xa active site. A number of small molecule
inhibitors have also recently been reported which appear to take advantage of a unique cation-π S4-site
available in Factor Xa to achieve good selectivity with moderate potency. The availbility of the X-ray
structure of native Factor Xa has allowed molecular modeling approaches to suggest possible fits of
these inhibitors to the Factor Xa active site.
Note Added in Proof
After this review was written, the x-ray structure of Factor Xa with DX-9065a was reported [81].
References
1. Proteinase inhibitors. In: Barrett AJ, Salvesen G, eds. Research Monographs in Cell and Tissue
Physiology. Vol 12. New York: Elsevier, 1986. Design of Enzyme Inhibitors as Drugs. Sandler M,
Smith HJ, eds. New York: Oxford University Press, 1989.
2. Colman RW, Hirsh J, Marder VJ, Salzman EW. Hemostasis and Thrombosis. Basic Principles and
Clinical Practice. Second Edition. Philadelphia: J. B. Lippincott Company, 1987.
3. Hathaway, WE, Goodnight, Jr SH. Disorders of Hemostasis and Thrombosis. New York: McGraw-
Hill, 1993.
4. Padmanabhan K, Padmanabhan KP, Tulinsky A, Park CH, Bode W, Huber R, Blankenship DT,
Cardin AD, Kisiel W. Structure of human Des(1–45) factor Xa at 2.2 Å resolution. J Mol Biol 1993;
232:947–966.
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