High Resolution Structural Studies of Drugs and the Complexes formed with Proteins, Enzymes, Receptors

Researchers from the Victorian College of Pharmacy and their collaborators have been able to achieve the limit in ultra-high resolution and molecular size to study the structure of an enzyme in complex with a drug, and have recently reported a structure at one of the highest resolutions ever for an enzyme-drug complex (Proteins 55: 805-813, 2004).

Ossama El-Kabbani, Roland Chung and the Nano-Litre Protein Crystallisation Facility for Rational Drug Design

High resolution crystal structure determinations of protein and enzyme targets, along with their binary and ternary complexes with coenzymes and inhibitors, such as

• Glutamate decarboxylase/antibody complex involved in autoimmunity and vaccine development.
• Members of the aldo-keto reductase super-family of enzymes implicated in diabetes and termination of pregnancy
• The T-cell antigen CD26 implicated in type II diabetes. Accurate structural information thus obtained will more readily facilitate the iterative process of ligand design.

Magdy Iskander and Jalal Jazayeri

The development of anti-inflammatory drugs via antagonism of cytokines as a primary target for treating inflammatory diseases, in particular:

• Development of drugs for Irritable Bowel Syndrome by determination of the structure complementarity of the ligand and its receptor.
• Understanding the mechanism of activation of mitoxantrone in tumour cells, through determination of the structure of mitoxantrone-DNA adducts.
• Development drugs for type II diabetes from the crystal structure of newly discovered phosphodiesterase isoforms.

Martin Scanlon

Determination of the structures of drug-protein complexes using both NMR spectroscopy and X-ray crystallography, in particular to investigate:

• The role of fatty acid binding proteins in the binding and transport of lipophilic drugs.
• DsbA as a target for the design of selective inhibitors of oxidative protein folding in Gram-negative bacteria.

Philip Thompson

• Design and synthesis of phosphodiesterase inhibitors. (This family of enzymes has been the subject of five published X-ray structures since 2000, most of these include a bound inhibitor).
• Studies of Ligands Bound to HIV Integrase. (One published X-ray structure of ligand -protein complex).
• Ligands for G-protein coupled receptors. (At present just a single member of this protein family, rhodopsin has been solved, though this is a major current endeavour).

David Chalmers

• Receptor-based design, in which the known three-dimensional structure of a target receptor is used to design compounds to interact with the macromolecule.
• Mechanism-based design, in which the known or anticipated catalytic mechanism of a target enzyme is used to design enzyme-selective inhibitors.
• Analogue-based design starts from the structures of known drugs and uses computer techniques to determine the structural features necessary for biological activity. Analogues with potential for enhanced activity may then be designed in silico.