Drug discovery proteins

Therapeutic target identification and validation is a key problem for drug discovery. Protein interactions and pathway analysis provide clues for identifying proteins that may be key control points within a pathology. Where protein-protein interactions are involved, there is potentially an all-against-all problem to be resolved to pinpoint the interacting proteins. 

Stout, T. J., Foster, P. G., Matthews, D. J. High-throughput shuctural biology in drug discovery protein kinases. Curr. Pharm Design, 2004,10, 1069-1082. 

Drug discovery protein-ligand interactions and protein-ligand docking... 

Cambridge Structural Database De Novo Ligand Design Pharmacophore and Drug Discovery Protein Data Bank (PDB) A Database of 3D Structural Information of Biological Macromolecules Structure Databases Three-dimensional Structure Generation Automation Three-dimensional Structure Searching. 

Previously, pharmacologists were constrained to the prewired sensitivity of isolated tissues for agonist study. As discussed in Chapter 2, different tissues possess different densities of receptor, different receptor co-proteins in the membranes, and different efficiencies of stimulus-response mechanisms. Judicious choice of tissue type could yield uniquely useful pharmacologic systems (i.e., sensitive screening tissues). However, before the availability of recombinant systems these choices were limited. With the ability to express different densities of human target proteins such as receptors has come a transformation in drug discovery. Recombinant cellular systems can now... 

Teague S. J. (2003). Implications of protein flexibility for drug discovery. Nature Reviews Drug Discovery 2 527-541. 

Pommier Y, Cherfils J (2005) Interfacial protein inhibition a nature s paradigm for drug discovery. Trends Pharmacol Sci 28 136 4-5... 

Akritopoulou-Zanze I (2006) The identification of new protein kinase inhibitors as targets in modern drug discovery. ID rugs 9 481-487... 

Bodovitz S, Joos T, Bachmann J. Protein biochips the calm before the storm. Drug Discovery Today 2005 10 283-7, 2005. 

This chapter consists of four main sections. The first provides an overall description of the process of contemporary protein structure determination by X-ray crystallography and summarizes the current computational requirements. This is followed by a summary and examples of the use of structure-based methods in drug discovery. The third section reviews the key developments in computer hardware and computational methods that have supported the development and application of X-ray crystallography over the past forty or so years. The final section outlines the areas in which improved... 

For many proteins, it is possible to generate structures of protein-ligand complexes quite rapidly. It is therefore not uncommon for many hundreds of structures to be determined in support of a drug discovery and optimization project. The major challenge for this level of throughput is informatics support. It is also this type of crystallography that is most in need of semiautomated procedures for structure solution and model building (see Section 12.6). 

THE CHALLENGES OF MAKING USEFUL PROTEIN-LIGAND FREE ENERGY PREDICTIONS FOR DRUG DISCOVERY... 

Babine RE, Abdel-Meguid SS. Protein crystallography in drug discovery (Vol. 20 of Mannhold R, Kubinyi H, Folkers G, editors. Methods and Principles in Medicinal Chemistry). Weinheim Wiley-VCH, 2004. 

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