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Professor Barry Potter
Professor Barry Potter
Complete protein-small molecule structure
Complete protein-small molecule structure
Binding site for the novel molecule
Binding site for the novel molecule
Cover of ACS Chemical Biology
Cover of ACS Chemical Biology

Internal News - 04 May 2007

Chemical biology team reports new molecular complex of drug target

A research paper by scientists from the universities of Bath and Dundee has thrown light upon the molecular detail of a fundamental recognition process involved in cell signalling.

Protein kinase B (PKB), in association with the protein complex PI3 kinase, is an important cell signalling system and its misregulation has been implicated in the development of numerous cancers. The protein is currently a popular drug target in the pharmaceutical industry.

Strategies to inhibit PKB have mainly focused on blocking activity in the region of its structure responsible for binding the energy molecule Adenosine Triphosphate (ATP). However, PKB contains another important site, the pleckstrin homology (PH) domain, which interacts with an internal cell surface signaling molecule to lead to PKB’s activation.

Once active, PKB sends signals to other proteins within the cell to promote both proliferation and survival. One such target is the protein cyclin D1 and over-expression of this protein has been associated with development of breast cancer.

Almost all efforts to design PKB inhibitors have focused on the ATP-binding domain, but the sheer number of ATP-binding proteins in the cell make it challenging to create specific inhibitors.

Instead, the Bath-Dundee group focused their attention on the PH domain of PKB. Using this, they have been able to design and synthesise a small-molecule that mimics a fragment of the molecule it normally recognises and solve the structure of the complex by X-ray crystallography.

This is the first time that any non-natural molecule has been shown to join or ‘complex’ effectively with this site of the drug target.

Importantly, it was also possible for the team to predict success using computer simulation or 'docking’, suggesting that other compounds could be designed and evaluated in silico as inhibitors of PKB function or as potential future drugs.

"Cellular signalling processes underpin a vast amount of modern biology,” said Professor Barry Potter from the Department of Pharmacy & Pharmacology at the University of Bath who led the team.

“Such compounds are useful pharmacological tools for studying signalling pathways in cells and can expose novel pathways for drug design.

“Designing ‘tailor-made’ chemical compounds that can interfere with cellular processes is a highly topical and important part of modern drug design that fits perfectly within the scientific mission of our department and the Medicinal Chemistry group in particular.

“The Department of Pharmacy & Pharmacology is investing strategically in chemical biology to encourage more such interactive partnerships between chemical and biological colleagues.

“Work such as this is only really possible through interdisciplinary collaboration between synthetic chemists, pharmacologists, computational chemists and X-ray crystallographers.

“One of the current major challenges in the life sciences is to make synergistic use of many different individual disciplines to a common end: the understanding of biology in terms of chemistry.”

The paper Novel Inositol Phospholipid Headgroup Surrogate Crystallized in the Pleckstrin Homology Domain of Protein Kinase Bα, was published in the April edition of the prestigious new American Chemical Society journal ACS Chemical Biology.

This journal was founded to help drive the exciting new field of chemical biology which is not just interdisciplinary, but often multidisciplinary.

The work was also featured on the cover of the journal, using a kaleidoscopic interpretation of the Bath molecule isolated from the experimental structure by computer modeling as a stick model with electron density mesh.

The research team includes: Dr Steve Mills, a synthetic medicinal chemist, Dr Steve Safrany, a pharmacologist, Dr Melanie Trusselle, a computational molecular modeller (all from the University of Bath), and Dr David Komander and Professor Daan van Aalten from the University of Dundee.

The research at the University of Bath was funded by a Wellcome Trust programme grant.