7 research outputs found
Actin–Curcumin Interaction: Insights into the Mechanism of Actin Polymerization Inhibition
Curcumin, derived from rhizomes of
the <i>Curcuma longa</i> plant, is known to possess a wide
range of medicinal properties.
We have examined the interaction of curcumin with actin and determined
their binding and thermodynamic parameters using isothermal titration
calorimetry. Curcumin is weakly fluorescent in aqueous solution, and
binding to actin enhances fluorescence several fold with a large blue
shift in the emission maximum. Curcumin inhibits microfilament formation,
which is similar to its role in inhibiting microtubule formation.
We synthesized a series of stable curcumin analogues to examine their
affinity for actin and their ability to inhibit actin self-assembly.
Results show that curcumin is a ligand with two symmetrical halves,
each of which possesses no activity individually. Oxazole, pyrazole,
and acetyl derivatives are less effective than curcumin at inhibiting
actin self-assembly, whereas a benzylidiene derivative is more effective.
Cell biology studies suggest that disorganization of the actin network
leads to destabilization of filaments in the presence of curcumin.
Molecular docking reveals that curcumin binds close to the cytochalasin
binding site of actin. Further molecular dynamics studies reveal a
possible allosteric effect in which curcumin binding at the “barbed
end” of actin is transmitted to the “pointed end”,
where conformational changes disrupt interactions with the adjacent
actin monomer to interrupt filament formation. Finally, the recognition
and binding of actin by curcumin is yet another example of its unique
ability to target multiple receptors
Actin–Curcumin Interaction: Insights into the Mechanism of Actin Polymerization Inhibition
Curcumin, derived from rhizomes of
the <i>Curcuma longa</i> plant, is known to possess a wide
range of medicinal properties.
We have examined the interaction of curcumin with actin and determined
their binding and thermodynamic parameters using isothermal titration
calorimetry. Curcumin is weakly fluorescent in aqueous solution, and
binding to actin enhances fluorescence several fold with a large blue
shift in the emission maximum. Curcumin inhibits microfilament formation,
which is similar to its role in inhibiting microtubule formation.
We synthesized a series of stable curcumin analogues to examine their
affinity for actin and their ability to inhibit actin self-assembly.
Results show that curcumin is a ligand with two symmetrical halves,
each of which possesses no activity individually. Oxazole, pyrazole,
and acetyl derivatives are less effective than curcumin at inhibiting
actin self-assembly, whereas a benzylidiene derivative is more effective.
Cell biology studies suggest that disorganization of the actin network
leads to destabilization of filaments in the presence of curcumin.
Molecular docking reveals that curcumin binds close to the cytochalasin
binding site of actin. Further molecular dynamics studies reveal a
possible allosteric effect in which curcumin binding at the “barbed
end” of actin is transmitted to the “pointed end”,
where conformational changes disrupt interactions with the adjacent
actin monomer to interrupt filament formation. Finally, the recognition
and binding of actin by curcumin is yet another example of its unique
ability to target multiple receptors
Discrimination of Ligands with Different Flexibilities Resulting from the Plasticity of the Binding Site in Tubulin
Tubulin, an α,β heterodimer, has four distinct
ligand
binding sites (for paclitaxel, peloruside/laulimalide, vinca, and
colchicine). The site where colchicine binds is a promising drug target
for arresting cell division and has been observed to accommodate compounds
that are structurally diverse but possess comparable affinity. This
investigation, using two such structurally different ligands as probes
(one being colchicine itself and another, TN16), aims to provide insight
into the origin of this diverse acceptability to provide a better
perspective for the design of novel therapeutic molecules. Thermodynamic
measurements reveal interesting interplay between entropy and enthalpy.
Although both these parameters are favourable for TN16 binding (Δ<i>H</i> < 0, Δ<i>S</i> > 0), but the magnitude
of entropy has the determining role for colchicine binding as its
enthalpic component is destabilizing (Δ<i>H</i> >
0, Δ<i>S</i> > 0). Molecular dynamics simulation
provides
atomistic insight into the mechanism, pointing to the inherent flexibility
of the binding pocket that can drastically change its shape depending
on the ligand that it accepts. Simulation shows that in the complexed
states both the ligands have freedom to move within the binding pocket;
colchicine can switch its interactions like a “flying trapeze”,
whereas TN16 rocks like a “swing cradle”, both benefiting
entropically, although in two different ways. Additionally, the experimental
results with respect to the role of solvation entropy correlate well
with the computed difference in the hydration: water molecules associated
with the ligands are released upon complexation. The complementary
role of van der Waals packing versus flexibility controls the entropy–enthalpy
modulations. This analysis provides lessons for the design of new
ligands that should balance between the “better fit”
and “flexibility”’, instead of focusing only
on the receptor–ligand interactions
Discrimination of Ligands with Different Flexibilities Resulting from the Plasticity of the Binding Site in Tubulin
Tubulin, an α,β heterodimer, has four distinct
ligand
binding sites (for paclitaxel, peloruside/laulimalide, vinca, and
colchicine). The site where colchicine binds is a promising drug target
for arresting cell division and has been observed to accommodate compounds
that are structurally diverse but possess comparable affinity. This
investigation, using two such structurally different ligands as probes
(one being colchicine itself and another, TN16), aims to provide insight
into the origin of this diverse acceptability to provide a better
perspective for the design of novel therapeutic molecules. Thermodynamic
measurements reveal interesting interplay between entropy and enthalpy.
Although both these parameters are favourable for TN16 binding (Δ<i>H</i> < 0, Δ<i>S</i> > 0), but the magnitude
of entropy has the determining role for colchicine binding as its
enthalpic component is destabilizing (Δ<i>H</i> >
0, Δ<i>S</i> > 0). Molecular dynamics simulation
provides
atomistic insight into the mechanism, pointing to the inherent flexibility
of the binding pocket that can drastically change its shape depending
on the ligand that it accepts. Simulation shows that in the complexed
states both the ligands have freedom to move within the binding pocket;
colchicine can switch its interactions like a “flying trapeze”,
whereas TN16 rocks like a “swing cradle”, both benefiting
entropically, although in two different ways. Additionally, the experimental
results with respect to the role of solvation entropy correlate well
with the computed difference in the hydration: water molecules associated
with the ligands are released upon complexation. The complementary
role of van der Waals packing versus flexibility controls the entropy–enthalpy
modulations. This analysis provides lessons for the design of new
ligands that should balance between the “better fit”
and “flexibility”’, instead of focusing only
on the receptor–ligand interactions
Discrimination of Ligands with Different Flexibilities Resulting from the Plasticity of the Binding Site in Tubulin
Tubulin, an α,β heterodimer, has four distinct
ligand
binding sites (for paclitaxel, peloruside/laulimalide, vinca, and
colchicine). The site where colchicine binds is a promising drug target
for arresting cell division and has been observed to accommodate compounds
that are structurally diverse but possess comparable affinity. This
investigation, using two such structurally different ligands as probes
(one being colchicine itself and another, TN16), aims to provide insight
into the origin of this diverse acceptability to provide a better
perspective for the design of novel therapeutic molecules. Thermodynamic
measurements reveal interesting interplay between entropy and enthalpy.
Although both these parameters are favourable for TN16 binding (Δ<i>H</i> < 0, Δ<i>S</i> > 0), but the magnitude
of entropy has the determining role for colchicine binding as its
enthalpic component is destabilizing (Δ<i>H</i> >
0, Δ<i>S</i> > 0). Molecular dynamics simulation
provides
atomistic insight into the mechanism, pointing to the inherent flexibility
of the binding pocket that can drastically change its shape depending
on the ligand that it accepts. Simulation shows that in the complexed
states both the ligands have freedom to move within the binding pocket;
colchicine can switch its interactions like a “flying trapeze”,
whereas TN16 rocks like a “swing cradle”, both benefiting
entropically, although in two different ways. Additionally, the experimental
results with respect to the role of solvation entropy correlate well
with the computed difference in the hydration: water molecules associated
with the ligands are released upon complexation. The complementary
role of van der Waals packing versus flexibility controls the entropy–enthalpy
modulations. This analysis provides lessons for the design of new
ligands that should balance between the “better fit”
and “flexibility”’, instead of focusing only
on the receptor–ligand interactions
Discrimination of Ligands with Different Flexibilities Resulting from the Plasticity of the Binding Site in Tubulin
Tubulin, an α,β heterodimer, has four distinct
ligand
binding sites (for paclitaxel, peloruside/laulimalide, vinca, and
colchicine). The site where colchicine binds is a promising drug target
for arresting cell division and has been observed to accommodate compounds
that are structurally diverse but possess comparable affinity. This
investigation, using two such structurally different ligands as probes
(one being colchicine itself and another, TN16), aims to provide insight
into the origin of this diverse acceptability to provide a better
perspective for the design of novel therapeutic molecules. Thermodynamic
measurements reveal interesting interplay between entropy and enthalpy.
Although both these parameters are favourable for TN16 binding (Δ<i>H</i> < 0, Δ<i>S</i> > 0), but the magnitude
of entropy has the determining role for colchicine binding as its
enthalpic component is destabilizing (Δ<i>H</i> >
0, Δ<i>S</i> > 0). Molecular dynamics simulation
provides
atomistic insight into the mechanism, pointing to the inherent flexibility
of the binding pocket that can drastically change its shape depending
on the ligand that it accepts. Simulation shows that in the complexed
states both the ligands have freedom to move within the binding pocket;
colchicine can switch its interactions like a “flying trapeze”,
whereas TN16 rocks like a “swing cradle”, both benefiting
entropically, although in two different ways. Additionally, the experimental
results with respect to the role of solvation entropy correlate well
with the computed difference in the hydration: water molecules associated
with the ligands are released upon complexation. The complementary
role of van der Waals packing versus flexibility controls the entropy–enthalpy
modulations. This analysis provides lessons for the design of new
ligands that should balance between the “better fit”
and “flexibility”’, instead of focusing only
on the receptor–ligand interactions
Discrimination of Ligands with Different Flexibilities Resulting from the Plasticity of the Binding Site in Tubulin
Tubulin, an α,β heterodimer, has four distinct
ligand
binding sites (for paclitaxel, peloruside/laulimalide, vinca, and
colchicine). The site where colchicine binds is a promising drug target
for arresting cell division and has been observed to accommodate compounds
that are structurally diverse but possess comparable affinity. This
investigation, using two such structurally different ligands as probes
(one being colchicine itself and another, TN16), aims to provide insight
into the origin of this diverse acceptability to provide a better
perspective for the design of novel therapeutic molecules. Thermodynamic
measurements reveal interesting interplay between entropy and enthalpy.
Although both these parameters are favourable for TN16 binding (Δ<i>H</i> < 0, Δ<i>S</i> > 0), but the magnitude
of entropy has the determining role for colchicine binding as its
enthalpic component is destabilizing (Δ<i>H</i> >
0, Δ<i>S</i> > 0). Molecular dynamics simulation
provides
atomistic insight into the mechanism, pointing to the inherent flexibility
of the binding pocket that can drastically change its shape depending
on the ligand that it accepts. Simulation shows that in the complexed
states both the ligands have freedom to move within the binding pocket;
colchicine can switch its interactions like a “flying trapeze”,
whereas TN16 rocks like a “swing cradle”, both benefiting
entropically, although in two different ways. Additionally, the experimental
results with respect to the role of solvation entropy correlate well
with the computed difference in the hydration: water molecules associated
with the ligands are released upon complexation. The complementary
role of van der Waals packing versus flexibility controls the entropy–enthalpy
modulations. This analysis provides lessons for the design of new
ligands that should balance between the “better fit”
and “flexibility”’, instead of focusing only
on the receptor–ligand interactions