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Lipophilicity and protein binding as key
descriptors for ADME behaviour and for a powerful ADME prediction software tool
Thomas Müller, Thorsten Hartmann, Johannes
Schmitt,
Nimbus Biotechnologie GmbH,
Eilenburger Str. 4, D-04317 Leipzig, Germany,
info@nimbus-biotech.com
Latest innovations in combinatorial chemistry and robotics provide increasing
numbers of lead compounds. Selecting candidates with appropriate physicochemical
properties in an early drug discovery phase is important to save money, time and
resources. All techniques for the characterization of so-called ADME behaviour
have several limitations, they remain time-consuming and resource-intensive.
This talk shows in-vitro assays for the determination of lipophilicity and
protein binding and a powerful ADME prediction software tool that is based on
this parameters to overcome these restrictions in a very simple way.
The binding of pharmaceutically relevant molecules to neutral or ionic lipid
membranes (expressed as the lipid/water partition coefficient log DLipid/Water)
is directly related to permeation and intestinal absorption, while the binding
of compounds to serum proteins like human serum albumin (HSA) determines the
bound fraction (fb) in the blood, thus affecting compound
distribution. The proprietary TRANSIL® technology, based on lipids
and proteins on solid supports, allows a fully automated assessment of both
parameters in conventional 96 or 384 well microtiter plates on a high throughput
scale.
TRANSIL® beads are functionalized with either a well-defined single
lipid-bilayer, which is non-covalently attached, or with HSA, immobilized on a
passivated surface. Utilizing these beads, the assay is performed in a simple
set-up without using special laboratory equipment. First, the compound of
interest is added to TRANSIL® ready-to-go plates. After a short
incubation TRANSIL® is easily separated by low speed centrifugation
of the plate or by filtration after transfer of the bead suspension to a
conventional filter plate. Using UV read-out the assay time is less than one
minute per compound. Both 96 and 384 well plate formats are supported allowing
high-throughput measurement of drug candidates.
The TRANSIL® approach was validated by comparison with conventional
techniques. The lipid-covered beads show high stability and are available with
different lipid compositions, modelling several membrane systems in the human
body. Both affinity parameters are key descriptors for two powerful ADME
prediction software packages (PK-Sim® and PK-Map™)
developed by Bayer Technology Services, so the determination of important
descriptors for bioavailability is reduced to easily accessible physicochemical
parameters. |
for
Physical Chemists by Physical Chemists
