5 research outputs found
Free Energy Profile Decomposition Analysis for QM/MM Simulations of Enzymatic Reactions
In
enzyme mechanistic studies and mutant design, it is highly desirable
to know the individual residue contributions to the reaction free
energy and barrier. In this work, we show that such free energy contributions
from each residue can be readily obtained by postprocessing ab initio quantum mechanical molecular mechanical (ai-QM/MM)
free energy simulation trajectories. Specifically, through a mean
force integration along the minimum free energy pathway, one can obtain
the electrostatic, polarization, and van der Waals contributions from
each residue to the free energy barrier. Separately, a similar analysis
procedure allows us to assess the contribution from different collective
variables along the reaction coordinate. The chorismate mutase reaction
is used to demonstrate the utilization of these two trajectory analysis
tools
Preclinical Evaluation of Novel Positron Emission Tomography (PET) Probes for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2)
Parkinson’s
disease (PD) is one of the most highly debilitating
neurodegenerative disorders, which affects millions of people worldwide,
and leucine-rich repeat kinase 2 (LRRK2) mutations have been involved
in the pathogenesis of PD. Developing a potent LRRK2 positron emission
tomography (PET) tracer would allow for in vivo visualization of LRRK2
distribution and expression in PD patients. In this work, we present
the facile synthesis of two potent and selective LRRK2 radioligands
[11C]3 ([11C]PF-06447475) and [18F]4 ([18F]PF-06455943). Both radioligands
exhibited favorable brain uptake and specific bindings in rodent autoradiography
and PET imaging studies. More importantly, [18F]4 demonstrated significantly higher brain uptake in the transgenic
LRRK2-G2019S mutant and lipopolysaccharide (LPS)-injected mouse models.
This work may serve as a roadmap for the future design of potent LRRK2
PET tracers
Preclinical Evaluation of Novel Positron Emission Tomography (PET) Probes for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2)
Parkinson’s
disease (PD) is one of the most highly debilitating
neurodegenerative disorders, which affects millions of people worldwide,
and leucine-rich repeat kinase 2 (LRRK2) mutations have been involved
in the pathogenesis of PD. Developing a potent LRRK2 positron emission
tomography (PET) tracer would allow for in vivo visualization of LRRK2
distribution and expression in PD patients. In this work, we present
the facile synthesis of two potent and selective LRRK2 radioligands
[11C]3 ([11C]PF-06447475) and [18F]4 ([18F]PF-06455943). Both radioligands
exhibited favorable brain uptake and specific bindings in rodent autoradiography
and PET imaging studies. More importantly, [18F]4 demonstrated significantly higher brain uptake in the transgenic
LRRK2-G2019S mutant and lipopolysaccharide (LPS)-injected mouse models.
This work may serve as a roadmap for the future design of potent LRRK2
PET tracers
Preclinical Evaluation of Novel Positron Emission Tomography (PET) Probes for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2)
Parkinson’s
disease (PD) is one of the most highly debilitating
neurodegenerative disorders, which affects millions of people worldwide,
and leucine-rich repeat kinase 2 (LRRK2) mutations have been involved
in the pathogenesis of PD. Developing a potent LRRK2 positron emission
tomography (PET) tracer would allow for in vivo visualization of LRRK2
distribution and expression in PD patients. In this work, we present
the facile synthesis of two potent and selective LRRK2 radioligands
[11C]3 ([11C]PF-06447475) and [18F]4 ([18F]PF-06455943). Both radioligands
exhibited favorable brain uptake and specific bindings in rodent autoradiography
and PET imaging studies. More importantly, [18F]4 demonstrated significantly higher brain uptake in the transgenic
LRRK2-G2019S mutant and lipopolysaccharide (LPS)-injected mouse models.
This work may serve as a roadmap for the future design of potent LRRK2
PET tracers
Preclinical Evaluation of Novel Positron Emission Tomography (PET) Probes for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2)
Parkinson’s
disease (PD) is one of the most highly debilitating
neurodegenerative disorders, which affects millions of people worldwide,
and leucine-rich repeat kinase 2 (LRRK2) mutations have been involved
in the pathogenesis of PD. Developing a potent LRRK2 positron emission
tomography (PET) tracer would allow for in vivo visualization of LRRK2
distribution and expression in PD patients. In this work, we present
the facile synthesis of two potent and selective LRRK2 radioligands
[11C]3 ([11C]PF-06447475) and [18F]4 ([18F]PF-06455943). Both radioligands
exhibited favorable brain uptake and specific bindings in rodent autoradiography
and PET imaging studies. More importantly, [18F]4 demonstrated significantly higher brain uptake in the transgenic
LRRK2-G2019S mutant and lipopolysaccharide (LPS)-injected mouse models.
This work may serve as a roadmap for the future design of potent LRRK2
PET tracers