Molecular Recognition in Biological Systems and Bioinformatics

Drug discovery; computer-aided-drug design; combinatorial chemistry; medicinal chemistry; molecular recognition.

Design and synthesis of protein kinase inhibitors as anti-cancer drugs, new methods, strategies and applications in combinatorial chemistry, and basic research in ligand-protein binding energetics

A broad-based protein kinase inhibitor discovery program is in progress that utilizes computer-aided-drug design and combinatorial synthetic chemistry technologies. These two technologies represent the most advanced "rational" and "empirical" approaches to drug discovery, respectively. Combining the two technologies provides a synergistic approach to drug discovery that is at the cutting edge of Medicinal Chemistry. Each of these technologies overcomes the main weakness of the other.

The human body contains around 2,000 different protein kinases. These enzymes catalyze the transfer of the terminal phosphate from ATP to their protein substrates by forming a phosphate linkage at tyrosine or serine residues. Protein kinases are intimately involved in cell signaling. They control events such as cell proliferation, cell movement and programmed cell death (apoptosis). Abnormally elevated activity of various protein kinases is involved in a number of diseases, including cancer. Consequently, inhibitors of these individual protein kinases have the potential to be useful drugs. Our lab is currently focused upon discovering inhibitors of the tyrosine kinase pp60c-src because this enzyme is linked to the survival of cancer cells but is not necessary for the survival of normal cells. Inhibitors of pp60c-src offer four potential utilities for treating cancer: 1) Inhibition of uncontrolled cancer cell proliferation, 2) Inhibition of metastasis, 3) Inhibition of tumor angiogenesis, and 4) Low toxicity.

We begin by designing prototype inhibitors of pp60c-src using molecular modeling and the crystal structures of various protein kinases. These initial inhibitors are then synthesized and tested for their biological activity. If the results are promising, a library of related inhibitors is designed, synthesized and tested. The synthesis of these libraries utilizes solid-supported combinatorial chemistry and an automated parallel reactor allowing 96 compounds to be simultaneously prepared.

Students and post-doctoral associates participate in the design, synthesis and interpretation of the biological activity of the compounds, thereby providing highly relevant training for a career in the pharmaceutical or biotechnology industry. Hands-on experience in combinatorial synthesis techniques is particularly sought after by employers in these industries. In addition, this training is received while working on a research project that has the potential to generate, in collaboration with industrial partners, drugs for serious diseases such as cancer. This project has a wide range of collaborators applying the latest molecular and cell biology technologies, including measuring gene expression profiles using DNA microarrays.

Other projects underway include the design and synthesis of novel scaffolds for the preparation of combinatorial libraries and basic research on the energetics of molecular recognition in biological assays.

Parallel synthesis combinatorial chemistry equipment

Drug modeling

Drug design

• Computer-aided-drug design
• Combinatorial chemistry
• Organic synthesis

http://www.chem.buffalo.edu/hangauer_publications.php