Protein structure-based methods

Protein Structure Based Methods for Compound Library Design... 

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... 

Kussell E, Shimada J, Shakhnovich EE A structure-based method for derivation of all-atom potentials for protein folding. Proc Natl Acad Sci USA 2002 99 5343-8. 

In general, ligand structure-based methods remain indispensable in those cases when the structure of binding site of the target protein is unknown. 

The abundance of structural information has led to a significant increase in the use of structure-based methods both to identify and to optimise inhibitors of protein kinases. The focus to date has centred upon small molecule ATP-competitive inhibitors and there are numerous examples of protein-ligand complexes available to guide design strategies. ATP binds in the cleft formed between the N- and C-terminal lobes of the protein kinase, forming several key interactions conserved across the protein kinase family. The adenine moiety lies in a hydrophobic region between the jS-sheet structure of subdomains I and II and residues from subdomains V and VIb. A... 

Methods that utilize structural data of the target, generally identified by protein crystallography, to look for molecules that complement the binding site through favorable protein-ligand interactions (protein structure-based VS or SBVS). 

A great variety of methods and techniques are now available for pharmacophore model generation. These methods are based on the appropriate choice of the ligand set (ligand-based, when much information is available on different ligand classes), and/or on one or more target/antitarget proteins (structure-based, particularly useful when... 

Fiser A, Sali A. 2003. Modeller generation and refinement of homology-based protein structure models. Methods Enzymol 374 461-491. 

A method for analyzing protein structure based on limited proteolysis. This method is especially useful in investigations of membrane proteins whose membrane association limits the repertoire of techniques that can be gainfully applied to infer structural features. For example, Davis et al used four proteases to assess the topology of yeast H -ATPase reconstituted into phosphatidyl-serine vesicles. Limited proteolysis by trypsin and a-chymotrypsin inactivates the enzyme and produces stable, membrane-bound fragments. Sequence analyses of... 

In this chapter, methods to derive hot spots and to translate them into real molecules are introduced. The approach is illustrated by using examples of successful protein structure-based virtual screening. 

Structure-based methods utilise information on the 3-D structure of the target protein. This information can be used as a template for docking experiments in which libraries of small molecules are fitted into the binding site of the target. The docking solutions are ranked by means of various scoring functions, leading to a hit list of potential binders. 

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