7 research outputs found
Unbinding Kinetics of Muscarinic M3 Receptor Antagonists Explained by Metadynamics Simulations
The residence time (RT), the time for which a drug remains
bound
to its biological target, is a critical parameter for drug design.
The prediction of this key kinetic property has been proven to be
challenging and computationally demanding in the framework of atomistic
simulations. In the present work, we setup and applied two distinct
metadynamics protocols to estimate the RTs of muscarinic M3 receptor
antagonists. In the first method, derived from the conformational
flooding approach, the kinetics of unbinding is retrieved from a physics-based
parameter known as the acceleration factor α (i.e., the running
average over time of the potential deposited in the bound state).
Such an approach is expected to recover the absolute RT value for
a compound of interest. In the second method, known as the tMETA‑D approach, a qualitative estimation
of the RT is given by the time of simulation required to drive the
ligand from the binding site to the solvent bulk. This approach has
been developed to reproduce the change of experimental RTs for compounds
targeting the same target. Our analysis shows that both computational
protocols are able to rank compounds in agreement with their experimental
RTs. Quantitative structure–kinetics relationship (SKR) models
can be identified and employed to predict the impact of a chemical
modification on the experimental RT once a calibration study has been
performed
Unbinding Kinetics of Muscarinic M3 Receptor Antagonists Explained by Metadynamics Simulations
The residence time (RT), the time for which a drug remains
bound
to its biological target, is a critical parameter for drug design.
The prediction of this key kinetic property has been proven to be
challenging and computationally demanding in the framework of atomistic
simulations. In the present work, we setup and applied two distinct
metadynamics protocols to estimate the RTs of muscarinic M3 receptor
antagonists. In the first method, derived from the conformational
flooding approach, the kinetics of unbinding is retrieved from a physics-based
parameter known as the acceleration factor α (i.e., the running
average over time of the potential deposited in the bound state).
Such an approach is expected to recover the absolute RT value for
a compound of interest. In the second method, known as the tMETA‑D approach, a qualitative estimation
of the RT is given by the time of simulation required to drive the
ligand from the binding site to the solvent bulk. This approach has
been developed to reproduce the change of experimental RTs for compounds
targeting the same target. Our analysis shows that both computational
protocols are able to rank compounds in agreement with their experimental
RTs. Quantitative structure–kinetics relationship (SKR) models
can be identified and employed to predict the impact of a chemical
modification on the experimental RT once a calibration study has been
performed
Unbinding Kinetics of Muscarinic M3 Receptor Antagonists Explained by Metadynamics Simulations
The residence time (RT), the time for which a drug remains
bound
to its biological target, is a critical parameter for drug design.
The prediction of this key kinetic property has been proven to be
challenging and computationally demanding in the framework of atomistic
simulations. In the present work, we setup and applied two distinct
metadynamics protocols to estimate the RTs of muscarinic M3 receptor
antagonists. In the first method, derived from the conformational
flooding approach, the kinetics of unbinding is retrieved from a physics-based
parameter known as the acceleration factor α (i.e., the running
average over time of the potential deposited in the bound state).
Such an approach is expected to recover the absolute RT value for
a compound of interest. In the second method, known as the tMETA‑D approach, a qualitative estimation
of the RT is given by the time of simulation required to drive the
ligand from the binding site to the solvent bulk. This approach has
been developed to reproduce the change of experimental RTs for compounds
targeting the same target. Our analysis shows that both computational
protocols are able to rank compounds in agreement with their experimental
RTs. Quantitative structure–kinetics relationship (SKR) models
can be identified and employed to predict the impact of a chemical
modification on the experimental RT once a calibration study has been
performed
Unbinding Kinetics of Muscarinic M3 Receptor Antagonists Explained by Metadynamics Simulations
The residence time (RT), the time for which a drug remains
bound
to its biological target, is a critical parameter for drug design.
The prediction of this key kinetic property has been proven to be
challenging and computationally demanding in the framework of atomistic
simulations. In the present work, we setup and applied two distinct
metadynamics protocols to estimate the RTs of muscarinic M3 receptor
antagonists. In the first method, derived from the conformational
flooding approach, the kinetics of unbinding is retrieved from a physics-based
parameter known as the acceleration factor α (i.e., the running
average over time of the potential deposited in the bound state).
Such an approach is expected to recover the absolute RT value for
a compound of interest. In the second method, known as the tMETA‑D approach, a qualitative estimation
of the RT is given by the time of simulation required to drive the
ligand from the binding site to the solvent bulk. This approach has
been developed to reproduce the change of experimental RTs for compounds
targeting the same target. Our analysis shows that both computational
protocols are able to rank compounds in agreement with their experimental
RTs. Quantitative structure–kinetics relationship (SKR) models
can be identified and employed to predict the impact of a chemical
modification on the experimental RT once a calibration study has been
performed
Unbinding Kinetics of Muscarinic M3 Receptor Antagonists Explained by Metadynamics Simulations
The residence time (RT), the time for which a drug remains
bound
to its biological target, is a critical parameter for drug design.
The prediction of this key kinetic property has been proven to be
challenging and computationally demanding in the framework of atomistic
simulations. In the present work, we setup and applied two distinct
metadynamics protocols to estimate the RTs of muscarinic M3 receptor
antagonists. In the first method, derived from the conformational
flooding approach, the kinetics of unbinding is retrieved from a physics-based
parameter known as the acceleration factor α (i.e., the running
average over time of the potential deposited in the bound state).
Such an approach is expected to recover the absolute RT value for
a compound of interest. In the second method, known as the tMETA‑D approach, a qualitative estimation
of the RT is given by the time of simulation required to drive the
ligand from the binding site to the solvent bulk. This approach has
been developed to reproduce the change of experimental RTs for compounds
targeting the same target. Our analysis shows that both computational
protocols are able to rank compounds in agreement with their experimental
RTs. Quantitative structure–kinetics relationship (SKR) models
can be identified and employed to predict the impact of a chemical
modification on the experimental RT once a calibration study has been
performed
Metadynamics Simulations Distinguish Short- and Long-Residence-Time Inhibitors of Cyclin-Dependent Kinase 8
The duration of drug efficacy in
vivo is a key aspect primarily
addressed during the lead optimization phase of drug discovery. Hence,
the availability of robust computational approaches that can predict
the residence time of a compound at its target would accelerate candidate
selection. Nowadays the theoretical prediction of this parameter is
still very challenging. Starting from methods reported in the literature,
we set up and validated a new metadynamics (META-D)-based protocol
that was used to rank the experimental residence times of 10 arylpyrazole
cyclin-dependent kinase 8 (CDK8) inhibitors for which target-bound
X-ray structures are available. The application of reported methods
based on the detection of the escape from the first free energy well
gave a poor correlation with the experimental values. Our protocol
evaluates the energetics of the whole unbinding process, accounting
for multiple intermediates and transition states. Using seven collective
variables (CVs) encoding both roto-translational and conformational
motions of the ligand, a history-dependent biasing potential is deposited
as a sum of constant-height Gaussian functions until the ligand reaches
an unbound state. The time required to achieve this state is proportional
to the integral of the deposited potential over the CV hyperspace.
Average values of this time, for replicated META-D simulations, provided
an accurate classification of CDK8 inhibitors spanning short, medium,
and long residence times
Discovery and Optimization of Thiazolidinyl and Pyrrolidinyl Derivatives as Inhaled PDE4 Inhibitors for Respiratory Diseases
Phosphodiesterase
4 (PDE4) is a key cAMP-metabolizing enzyme involved
in the pathogenesis of inflammatory disease, and its pharmacological
inhibition has been shown to exert therapeutic efficacy in chronic
obstructive pulmonary disease (COPD). Herein, we describe a drug discovery
program aiming at the identification of novel classes of potent PDE4
inhibitors suitable for pulmonary administration. Starting from a
previous series of benzoic acid esters, we explored the chemical space
in the solvent-exposed region of the enzyme catalytic binding pocket.
Extensive structural modifications led to the discovery of a number
of heterocycloalkyl esters as potent <i>in vitro</i> PDE4
inhibitors. (<i>S</i>*,<i>S</i>**)-<b>18e</b> and (<i>S</i>*,<i>S</i>**)-<b>22e</b>,
in particular, exhibited optimal <i>in vitro</i> ADME and
pharmacokinetics properties and dose-dependently counteracted acute
lung eosinophilia in an experimental animal model. The optimal biological
profile as well as the excellent solid-state properties suggest that
both compounds have the potential to be effective topical agents for
treating respiratory inflammatory diseases