13 research outputs found
Binding Free-Energy Calculation Is a Powerful Tool for Drug Optimization: Calculation and Measurement of Binding Free Energy for 7‑Azaindole Derivatives to Glycogen Synthase Kinase-3β
Present
computational lead (drug)-optimization is lacking in thermodynamic
tactics. To examine whether calculation of binding free-energy change
(Δ<i>G</i>) is effective for the lead-optimization
process, binding Δ<i>G</i>s of 7-azaindole derivatives
to the ATP binding site of glycogen synthase kinase-3β (GSK-3β)
were calculated. The result was a significant correlation coefficient
of <i>r</i> = 0.895 between calculated and observed Δ<i>G</i>s. This indicates that calculated Δ<i>G</i> reflects the inhibitory activities of 7-azaindole derivatives. In
addition to quantitative estimation of activity, Δ<i>G</i> calculation characterizes the thermodynamic behavior of 7-azaindole
derivatives, providing also useful information for inhibitor optimization
on affinity to water molecules
Discovery of Highly Potent and Selective Matrix Metalloproteinase‑7 Inhibitors by Hybridizing the S1′ Subsite Binder with Short Peptides
Matrix metalloproteinase-7 (MMP-7) has emerged as a protein
playing
important roles in both physiological and pathophysiological processes.
Despite the growing interest in MMP-7 as a potential therapeutic target
for diseases including cancer and fibrosis, potent and selective MMP-7
inhibitors have yet to be identified. Compound 1, previously
reported by Edman and co-workers, binds to the S1′ subsite
of MMP-7, exhibiting moderate inhibitory activity and selectivity.
To achieve both higher inhibitory activity and selectivity, we conceived
hybridizing 1 with short peptides. The initially designed
compound 6, which was a hybrid molecule between 1 and a tripeptide (Ala-Leu-Met) derived from an MMP-2-inhibitory
peptide (APP-IP), showed enhanced MMP-7-inhibitory activity. Subsequent
optimization of the peptide moiety led to the development of compound 18 with remarkable potency for MMP-7 and selectivity over
other MMP subtypes
Discovery of Highly Potent and Selective Matrix Metalloproteinase‑7 Inhibitors by Hybridizing the S1′ Subsite Binder with Short Peptides
Matrix metalloproteinase-7 (MMP-7) has emerged as a protein
playing
important roles in both physiological and pathophysiological processes.
Despite the growing interest in MMP-7 as a potential therapeutic target
for diseases including cancer and fibrosis, potent and selective MMP-7
inhibitors have yet to be identified. Compound 1, previously
reported by Edman and co-workers, binds to the S1′ subsite
of MMP-7, exhibiting moderate inhibitory activity and selectivity.
To achieve both higher inhibitory activity and selectivity, we conceived
hybridizing 1 with short peptides. The initially designed
compound 6, which was a hybrid molecule between 1 and a tripeptide (Ala-Leu-Met) derived from an MMP-2-inhibitory
peptide (APP-IP), showed enhanced MMP-7-inhibitory activity. Subsequent
optimization of the peptide moiety led to the development of compound 18 with remarkable potency for MMP-7 and selectivity over
other MMP subtypes
Discovery of Highly Potent and Selective Matrix Metalloproteinase‑7 Inhibitors by Hybridizing the S1′ Subsite Binder with Short Peptides
Matrix metalloproteinase-7 (MMP-7) has emerged as a protein
playing
important roles in both physiological and pathophysiological processes.
Despite the growing interest in MMP-7 as a potential therapeutic target
for diseases including cancer and fibrosis, potent and selective MMP-7
inhibitors have yet to be identified. Compound 1, previously
reported by Edman and co-workers, binds to the S1′ subsite
of MMP-7, exhibiting moderate inhibitory activity and selectivity.
To achieve both higher inhibitory activity and selectivity, we conceived
hybridizing 1 with short peptides. The initially designed
compound 6, which was a hybrid molecule between 1 and a tripeptide (Ala-Leu-Met) derived from an MMP-2-inhibitory
peptide (APP-IP), showed enhanced MMP-7-inhibitory activity. Subsequent
optimization of the peptide moiety led to the development of compound 18 with remarkable potency for MMP-7 and selectivity over
other MMP subtypes
Discovery of Highly Potent and Selective Matrix Metalloproteinase‑7 Inhibitors by Hybridizing the S1′ Subsite Binder with Short Peptides
Matrix metalloproteinase-7 (MMP-7) has emerged as a protein
playing
important roles in both physiological and pathophysiological processes.
Despite the growing interest in MMP-7 as a potential therapeutic target
for diseases including cancer and fibrosis, potent and selective MMP-7
inhibitors have yet to be identified. Compound 1, previously
reported by Edman and co-workers, binds to the S1′ subsite
of MMP-7, exhibiting moderate inhibitory activity and selectivity.
To achieve both higher inhibitory activity and selectivity, we conceived
hybridizing 1 with short peptides. The initially designed
compound 6, which was a hybrid molecule between 1 and a tripeptide (Ala-Leu-Met) derived from an MMP-2-inhibitory
peptide (APP-IP), showed enhanced MMP-7-inhibitory activity. Subsequent
optimization of the peptide moiety led to the development of compound 18 with remarkable potency for MMP-7 and selectivity over
other MMP subtypes
Discovery of Highly Potent and Selective Matrix Metalloproteinase‑7 Inhibitors by Hybridizing the S1′ Subsite Binder with Short Peptides
Matrix metalloproteinase-7 (MMP-7) has emerged as a protein
playing
important roles in both physiological and pathophysiological processes.
Despite the growing interest in MMP-7 as a potential therapeutic target
for diseases including cancer and fibrosis, potent and selective MMP-7
inhibitors have yet to be identified. Compound 1, previously
reported by Edman and co-workers, binds to the S1′ subsite
of MMP-7, exhibiting moderate inhibitory activity and selectivity.
To achieve both higher inhibitory activity and selectivity, we conceived
hybridizing 1 with short peptides. The initially designed
compound 6, which was a hybrid molecule between 1 and a tripeptide (Ala-Leu-Met) derived from an MMP-2-inhibitory
peptide (APP-IP), showed enhanced MMP-7-inhibitory activity. Subsequent
optimization of the peptide moiety led to the development of compound 18 with remarkable potency for MMP-7 and selectivity over
other MMP subtypes
Discovery of Highly Potent and Selective Matrix Metalloproteinase‑7 Inhibitors by Hybridizing the S1′ Subsite Binder with Short Peptides
Matrix metalloproteinase-7 (MMP-7) has emerged as a protein
playing
important roles in both physiological and pathophysiological processes.
Despite the growing interest in MMP-7 as a potential therapeutic target
for diseases including cancer and fibrosis, potent and selective MMP-7
inhibitors have yet to be identified. Compound 1, previously
reported by Edman and co-workers, binds to the S1′ subsite
of MMP-7, exhibiting moderate inhibitory activity and selectivity.
To achieve both higher inhibitory activity and selectivity, we conceived
hybridizing 1 with short peptides. The initially designed
compound 6, which was a hybrid molecule between 1 and a tripeptide (Ala-Leu-Met) derived from an MMP-2-inhibitory
peptide (APP-IP), showed enhanced MMP-7-inhibitory activity. Subsequent
optimization of the peptide moiety led to the development of compound 18 with remarkable potency for MMP-7 and selectivity over
other MMP subtypes
Discovery of Highly Potent and Selective Matrix Metalloproteinase‑7 Inhibitors by Hybridizing the S1′ Subsite Binder with Short Peptides
Matrix metalloproteinase-7 (MMP-7) has emerged as a protein
playing
important roles in both physiological and pathophysiological processes.
Despite the growing interest in MMP-7 as a potential therapeutic target
for diseases including cancer and fibrosis, potent and selective MMP-7
inhibitors have yet to be identified. Compound 1, previously
reported by Edman and co-workers, binds to the S1′ subsite
of MMP-7, exhibiting moderate inhibitory activity and selectivity.
To achieve both higher inhibitory activity and selectivity, we conceived
hybridizing 1 with short peptides. The initially designed
compound 6, which was a hybrid molecule between 1 and a tripeptide (Ala-Leu-Met) derived from an MMP-2-inhibitory
peptide (APP-IP), showed enhanced MMP-7-inhibitory activity. Subsequent
optimization of the peptide moiety led to the development of compound 18 with remarkable potency for MMP-7 and selectivity over
other MMP subtypes
Discovery of TP0597850: A Selective, Chemically Stable, and Slow Tight-Binding Matrix Metalloproteinase‑2 Inhibitor with a Phenylbenzamide–Pentapeptide Hybrid Scaffold
Matrix metalloproteinase-2 (MMP2) is a zinc-dependent
endopeptidase
and a promising target for various diseases, including cancer and
fibrosis. Herein, we report the discovery of a novel MMP2-selective
inhibitor with high chemical stability and slow tight-binding features.
Based on the degradation mechanism of our small-molecule–peptide
hybrid 1, the tripeptide linker {5-aminopentanoic acid
[Ape(5)]–Glu–Asp} of 1 was replaced by
a shorter linker (γ-D-Glu). Phenylbenzamide was suitable for
the new generation of MMP2 inhibitors as an S1′ pocket-binding
group. The introduction of (4S)-aminoproline dramatically
increased the chemical stability while maintaining high subtype selectivity
because of its interaction with Glu130. TP0597850 (18) exhibited high stability over a wide range of pH values as well
as potent MMP2 inhibition (Ki = 0.034
nM) and ≥2000-fold selectivity determined using the inhibition
constants. A kinetic analysis revealed that it possesses slow tight-binding
nature with a long MMP2 dissociative half-life (t1/2 = 265 min)
Discovery of TP0597850: A Selective, Chemically Stable, and Slow Tight-Binding Matrix Metalloproteinase‑2 Inhibitor with a Phenylbenzamide–Pentapeptide Hybrid Scaffold
Matrix metalloproteinase-2 (MMP2) is a zinc-dependent
endopeptidase
and a promising target for various diseases, including cancer and
fibrosis. Herein, we report the discovery of a novel MMP2-selective
inhibitor with high chemical stability and slow tight-binding features.
Based on the degradation mechanism of our small-molecule–peptide
hybrid 1, the tripeptide linker {5-aminopentanoic acid
[Ape(5)]–Glu–Asp} of 1 was replaced by
a shorter linker (γ-D-Glu). Phenylbenzamide was suitable for
the new generation of MMP2 inhibitors as an S1′ pocket-binding
group. The introduction of (4S)-aminoproline dramatically
increased the chemical stability while maintaining high subtype selectivity
because of its interaction with Glu130. TP0597850 (18) exhibited high stability over a wide range of pH values as well
as potent MMP2 inhibition (Ki = 0.034
nM) and ≥2000-fold selectivity determined using the inhibition
constants. A kinetic analysis revealed that it possesses slow tight-binding
nature with a long MMP2 dissociative half-life (t1/2 = 265 min)