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Thomas Müller
Thomas Müller Jon Mole Karl Box


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,

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.

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Last modified: 28 April 2008