 |
PDBsum entry 4zpg
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase/hydrolase inhibitor
|
PDB id
|
|
|
|
4zpg
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Methyl-Substitution of an iminohydantoin spiropiperidine β-Secretase (bace-1) inhibitor has a profound effect on its potency.
|
|
|
Authors
|
|
M.Egbertson,
G.B.Mcgaughey,
S.M.Pitzenberger,
S.R.Stauffer,
C.A.Coburn,
S.J.Stachel,
W.Yang,
J.C.Barrow,
L.A.Neilson,
M.Mcwherter,
D.Perlow,
B.Fahr,
S.Munshi,
T.J.Allison,
K.Holloway,
H.G.Selnick,
Z.Yang,
J.Swestock,
A.J.Simon,
S.Sankaranarayanan,
D.Colussi,
K.Tugusheva,
M.T.Lai,
B.Pietrak,
S.Haugabook,
L.Jin,
I.W.Chen,
M.Holahan,
M.Stranieri-Michener,
J.J.Cook,
J.Vacca,
S.L.Graham.
|
|
|
Ref.
|
|
Bioorg Med Chem Lett, 2015,
25,
4812-4819.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The IC50 of a beta-secretase (BACE-1) lead compound was improved ∼200-fold
from 11μM to 55nM through the addition of a single methyl group. Computational
chemistry, small molecule NMR, and protein crystallography capabilities were
used to compare the solution conformation of the ligand under varying pH
conditions to its conformation when bound in the active site. Chemical
modification then explored available binding pockets adjacent to the ligand. A
strategically placed methyl group not only maintained the required pKa of the
piperidine nitrogen and filled a small hydrophobic pocket, but more importantly,
stabilized the conformation best suited for optimized binding to the receptor.
|
|
|
|
|
|
|
