 |
PDBsum entry 5c26
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transferase/inhibitor
|
PDB id
|
|
|
|
5c26
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Imidazotriazines: spleen tyrosine kinase (syk) inhibitors identified by free-Energy perturbation (fep).
|
|
|
Authors
|
|
F.Lovering,
C.Aevazelis,
J.Chang,
C.Dehnhardt,
L.Fitz,
S.Han,
K.Janz,
J.Lee,
N.Kaila,
J.Mcdonald,
W.Moore,
A.Moretto,
N.Papaioannou,
D.Richard,
M.S.Ryan,
Z.K.Wan,
A.Thorarensen.
|
|
|
Ref.
|
|
Chemmedchem, 2016,
11,
217-233.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
There has been significant interest in spleen tyrosine kinase (Syk) owing to its
role in a number of disease states, including autoimmunity, inflammation, and
cancer. Ongoing therapeutic programs have resulted in several compounds that are
now in clinical use. Herein we report our optimization of the imidazopyrazine
core scaffold of Syk inhibitors through the use of empirical and computational
approaches. Free-energy perturbation (FEP) methods with MCPRO+ were undertaken
to calculate the relative binding free energies for several alternate scaffolds.
FEP was first applied retrospectively to determine if there is any predictive
value; this resulted in 12 of 13 transformations being predicted in a
directionally correct manner. FEP was then applied in a prospective manner to
evaluate 17 potential targets, resulting in the realization of imidazotriazine
17 (3-(4-(3,4-dimethoxyphenylamino)imidazo[1,2-f][1,2,4]triazin-2-yl)benzamide),
which shows a tenfold improvement in activity relative to the parent compound
and no increase in atom count. Optimization of 17 led to compounds with
nanomolar cellular activity.
|
|
|
|
|
|
|
