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What we do...
Our research contributes to understanding of processes that affect the fates and effects of drugs in the body,
in terms of structures/properties of drugs and body components, using
bench-top and computational methods.
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Drug-Phospholipid
Interactions.
We are interested in drug transport and
accumulation in
hydrated headgroups, adsorbed phospholipid monolayers, and liposomes as
dependent on drug and phospholipid properties. The used methods include calorimetry, fluorescence spectroscopy, confocal fluorescence
microscopy, and molecular dynamics simulations. |
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Subcellular Pharmacokinetics describes the rate and extent of
drug disposition in the body. We study cellular drug transport and
accumulation using confocal fluorescence microscopy and (molecular)
modeling. The results are condensed in the disposition function
and form the basis for Quantitative Structure-Time-Activity
Relationships (QSTAR). |
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Similarity of MMPs (matrix
metalloproteinases) and other metzincins is analyzed using a grid- based
approach with superimposed. structures and comparative models of the
enzymes. Probes imitating the inhibitor and substrate atoms are placed
in grid points and interaction energies with flexible binding sites are
calculated using a force field. Comparative models are available for
download. |
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QM/MM Methods for Prediction of
Metalloprotein Affinities are meant to improve the description of
the coordination interactions between ligands and metals. We use a
four-tier approach including docking, QM/MM minimization, restricted MD
simulations, and single-point QM/MM energies to obtain correlations to
bench-top data. |
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Slow Inhibition Kinetics of
MMPs and other metzincins is studied using an organo-metallic
mimics of the catalytic zinc and isolated enzymes. We hypothesize that
the kinetics is given by interplay of the fast noncovalent step and the
potentially slow coordination step. The results are
interpreted and rationalized using computational models that are based
on QM/MM and MD methods. |
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Receptor-based Prediction
of Binding Affinities utilizes thorough conformational sampling of the
receptor-ligand complex structures by molecular dynamics and similar methods.
To correlate the simulation results with experimental data, we use the Linear Response approximation
with time-averages of relevant interaction energies
and work on its improvements. |
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Multi-species, Multi-mode
Protein-Ligand Binding has been developed for receptor-based and
ligand-based methods for prediction of binding affinities. We are
working on the Linear Response methods with this option. The
implementation in Comparative Molecular-field Analysis (CoMFA), the most
popular 3D-QSAR method, will be available soon to the Sybyl users. |
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Last Updated: June 15, 2005 |
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