Preface [hot topic: Protein Crystallography in Drug Design (guest editor: Jonathan B. Cooper)]
Cooper, J.B. (2004) Preface [hot topic: Protein Crystallography in Drug Design (guest editor: Jonathan B. Cooper)]. Current Drug Targets, 5, (2), p.i.
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he value of structure analysis of proteins in rational drug design is undisputed. The ability to visualize the three dimensional structure of a receptor or enzyme provides a unique view of the residues that make up the protein's ligand binding or catalytic site. The analysis of complexes with ligands or inhibitors provides many clues on the roles that these residues play in the functioning of the molecule. The information derived from this 'picture' can be used to design the next generation of inhibitors with improved complementarity to the ligand-binding site. Whilst many other considerations such as solubility, lipophilicity, chemical stability and bioavailability also 'shape' the drug design process, crystallography can assist in designing compounds which minimize the problems of resistance that arise, for example, when drugs are used to treat infections by viruses that undergo rapid mutation.
In this volume, Elspeth Garman (Oxford) and Graeme Laver (Canberra) describe the impact which structural studies have had on the design of influenza drugs. Despite the fact that influenza is a disease which affects millions of people, sometimes with fatal consequences, there has not, until recently, been any drug effective against all strains and vaccines may be relatively or totally ineffective. Screening of many thousands of compounds by pharmaceutical companies has resulted in only two compounds, amantadine and rimantidine, which target the M2 ion channel on the virus and these drugs have major disadvantages. Knowledge of the crystal structure of influenza virus neuraminidase, on the other hand, has allowed the rational design of four “plug-drugs” which bind to the active site of flu neuraminidase and stop replication of the virus. Two of these compounds, Relenza and Tamiflu, are now being used world wide and, although effective when used properly, suffer from problems of delivery. They need to be given very soon after infection to be effective, they only inhibit the influenza virus and none of the other respiratory agents which cause flu-like symptoms, and they are very expensive.
The review by Leo Brady and Gus Cameron (Bristol) details the application of protein crystallography and other structural techniques to identifying novel drug targets from plasmodia, the causative agent of malaria. The current use of structure-based design in developing effective drugs for plasmodial targets is discussed.
The review by Steve Wood and Simon Kolstoe (Southampton) summarises the known properties of amyloid fibres and proteins found associated with them. The role of X-ray crystallography in analyzing the amyloid proteins themselves and proteins that protect the fibres is discussed. In addition the analysis of complexes with compounds that inhibit fibre formation and compounds that inhibit the processing enzymes will be covered. In the next article, Chris Dealwis and Jonathan Wall (Knoxville) describe structural approaches to combating the pathogenicity of amyloid disease characterised by the deposition of monoclonal free immunoglobulin light chain proteins (LC) as amyloid fibrils within vital organs. Finally, in the review by Leighton Coates (Southampton) and Dean Myles (Grenoble), the manifold benefits of atomic resolution X-ray diffraction analysis of proteins are described. The ability to locate hydrogen atoms of interest and thus define the protonation states of many side chains including the active site groups is potentially of enormous benefit to the drug design process. In addition, the ability to improve definition of disordered regions of the molecule, to analyse ligands which bind with poor occupancy and to study anisotropic movements within the molecule provides further important data. Recent developments in neutron data collection mean that complementary information on proton positions can be provided for an increasing number of proteins. There are several hundred Xray crystal structures that have been refined to or beyond atomic resolution in the protein databank. A number of these structures are of proteins that are currently targets for drug discovery and these are surveyed to illustrate the benefits of atomic resolution X-ray analysis.
|Subjects:||R Medicine > RB Pathology
Q Science > QD Chemistry
R Medicine > RS Pharmacy and materia medica
|Divisions:||University Structure - Pre August 2011 > School of Biological Sciences
|Date Deposited:||08 Aug 2008|
|Last Modified:||27 Mar 2014 18:39|
|RDF:||RDF+N-Triples, RDF+N3, RDF+XML, Browse.|
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