 |
PDBsum entry 2bqw
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Probing the subpockets of factor xa reveals two binding modes for inhibitors based on a 2-Carboxyindole scaffold: a study combining structure-Activity relationship and x-Ray crystallography.
|
|
|
Authors
|
|
M.Nazaré,
D.W.Will,
H.Matter,
H.Schreuder,
K.Ritter,
M.Urmann,
M.Essrich,
A.Bauer,
M.Wagner,
J.Czech,
M.Lorenz,
V.Laux,
V.Wehner.
|
|
|
Ref.
|
|
J Med Chem, 2005,
48,
4511-4525.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Structure-activity relationships within a series of highly potent
2-carboxyindole-based factor Xa inhibitors incorporating a neutral P1 ligand are
described with particular emphasis on the structural requirements for addressing
subpockets of the factor Xa enzyme. Interactions with the subpockets were probed
by systematic substitution of the 2-carboxyindole scaffold, in combination with
privileged P1 and P4 substituents. Combining the most favorable substituents at
the indole nucleus led to the discovery of a remarkably potent factor Xa
inhibitor displaying a K(i) value of 0.07 nM. X-ray crystallography of
inhibitors bound to factor Xa revealed substituent-dependent switching of the
inhibitor binding mode and provided a rationale for the SAR obtained. These
results underscore the key role played by the P1 ligand not only in determining
the binding affinity of the inhibitor by direct interaction but also in
modifying the binding mode of the whole scaffold, resulting in a nonlinear SAR.
|
|
|
|
|
|
|
