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be utilized to model known Factor Xa inhibitors using the x-ray coordinates of native Factor Xa.
Preliminary modeling of the several inhibitors described below into the Factor Xa active site was
accomplished by the author [69] by first superimposing the backbone atoms (N, Ca, C) of the catalytic
triads (His 57, Asp 102, Ser 195 in the benzamidine:thrombin and PPACK:thrombin x-ray structures on the
corresponding residues in Factor Xa. This allowed an excellent fit of the P1 basic groups,
arylbenzamidine in the case of benzamidine and arginine for PPACK, into the S1 pocket of Factor Xa.
These groups were then used as templates for positioning the appropriate P1 basic groups of the various
synthetic inhibitors [69]. Holding these docked P1 groups fixed, the remaining rotatable bonds were
manipulated to allow a reasonable and complementary fit of the inhibitor atoms to the solvent accessible
surface of the Factor Xa active site. In those cases where it was possible, hydrogen bonds, particularly to
Gly 216, were formed. To fit extended peptide sequences such as that for antistasin and the antistasinderived
peptides described below, the backbone atoms of the residues around the cleavage site (e.g.,
P4–P4') were positioned using the corresponding BPTI backbone atoms as a template. This was done
after first aligning the trypsin catalytic triad backbone in the BPTI:trypsin x-ray complex (vida infra) to
Factor Xa. Where the side chains of the bound peptide segments differed from BPTI, their orientation
was either modeled for maximum complementarity to the Factor Xa molecular surface or set by an
algorithmic approach [78]. In some cases the structures obtained were energy minimized initially by
steepest descent followed by conjugate gradient minimization.
Recently, compounds based on a bisamidine motif (e.g., DX-9065a) have been reported as potent and
selective Factor Xa inhibitors (1, DX-9065a) [60–63].
The position of the amidino group makes little difference to the Factor Xa potency of these compounds
but, interestingly, has a dramatic effect on the selectivity towards thrombin [62]. It was also observed
that one carboxylic acid isomer (CX-9065a) was 7 times more potent on Factor Xa than the other. A
second set of analogs shows a similar SAR [60].
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