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Förslaget inkom 2004-02-02

Identification and development of dipeptide ligands

Biovitrum is one of Europe's largest biotechnology companies. Of our 530 employees, more than 420 are scientists. The company is active in the research and development of small molecule drugs and recombinant protein drugs, as well as the manufacture of recombinant protein drugs.
Drug research is concentrated on metabolic diseases, such as obesity and type 2 diabetes. The development of protein drugs is focused on metabolic diseases and oncology.

The Structural Chemistry department at Biovitrum is presently seeking a student well oriented in medicinal chemistry and with an interest in NMR and structural biology.

To use NMR techniques to identify binders to 3C protease from a set of dipeptides and to develop a binding dipeptide into small molecule ligands.

A critical aspect of the drug discovery process is the ability to reliably detect and identify small molecules which bind to macromolecular targets. Lately, the use of different NMR techniques as a binding assay for screening compound libraries has attracted considerable attention from the pharmaceutical industry. To detect binding, no information on the function of the target protein is necessary and it is possible to detect also very weak binders.

Peptides are unsuitable as orally administered drugs and are difficult to mimick with small organic molecules. However, if there is information on the binding mode and the peptide is very short (dipeptide) it should be possible to mimick by compounds with druglike properties. Further, dipeptides are highly soluble which is a prerequisite for most NMR techniques and flexible enough to adapt to the binding pocket of the target protein. There is a crystal structure of the 3C protease determined in-house.

To identify dipeptides that bind to the target protein, saturation transfer difference (STD) NMR spectroscopy should be used. Transfer NOE experiments are to be performed to obtain hydrogen-hydrogen distances within the bound dipeptide. The experimental data are to be used as input in docking studies, subsequent 3D-pharmacophore searches in the Biovitrum compound collection and finally to design and synthesise more restrained analogues. Attempts to crystallize complexes between 3C protease and ligands to determine the structure should be made. NMR binding assays will be used to confirm binding of compounds mimicking the dipeptide binding mode.

The primary goals of the project should be to:
·identify dipeptide ligands to a protein by means of STD NMR.
·determine hydrogen-hydrogen distances within the bound peptide by means of transfer NOE.
·use the obtained experimental results to develop a dipeptide ligand to small molecule ligands.

Contact person: Johan Schultz
Email: [email protected]
Address: Biovitrum, Structural Chemistry, 11276 Stockholm


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