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Modeling


Molecular Modeling is a method used for the development of new lead structures as well as for the optimization of the bioactivity and selectivity of new drugs. If the 3D-structures of the receptor proteins are known, the preferred techniques applied include docking, virtual screening and DeNovo design.

When the 3D-structure of a receptor is not available, similarly successful optimization can be achieved with the aid of ligand-based molecular design, particularly if it is possible to access a very extensive compilation of biological test results. In these cases, techniques like 3D-QSAR, ComFA or pharmacophor modeling are employed.

Ligand-based design for GAT inhibitors

The development of new subtype selective inhibitors of the GABA transporters mGAT1-mGAT4 is the central area of research of our group. As GABA transporters are membrane-bound proteins, no 3D structures are available for them at present. Our own section for biological screening provides a great variety of test results about the different subtypes of GABA transporters. These enable us to use ligand-based techniques of molecular modeling.

Using ComFA we are developing a field-based 3D-QSAR model that allows us to quickly and efficiently produce predictions both about new structures for inhibitors and structural concepts.

We use Catalyst to develop pharmacophor models of the different GABA-transporters to employ for fast screening of our own collection of substances and commercially available substance libraries. With the help of these models we can integrate new molecules in our own testing system with a minimum of expense and improve the proposed pharmacophor models through the new data.

Our theoretical work is aimed at finding molecules exhibiting a very high activity and selectivity for the different GABA-transporter subtypes.

Figure 1: (S)-SNAP in a pharmacophor model for GAT-3 inhibitors. (blue = hydrophobe, red = can be ionised positively, green= H-bridge acceptor)


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