Structure-Based Methods

Both ligand- and structure-based methods can be applied in virtual screening. An example of a workflow chart for virtual screening is depicted in Figure 10,4-3. 

An impressive example of the application of structure-based methods was the design of a inhibitor of the HIV protease by a group of scientists at DuPont Merck [Lam et al. 1994 This enzyme is crucial to the replication of the HIV virus, and inhibitors have bee shown to have therapeutic value as components of anti-AIDS treatment regimes. The star1 ing point for their work was a series of X-ray crystal structures of the enzyme with number of inhibitors boimd. Their objective was to discover potent, novel leads whid were orally available. Many of the previously reported inhibitors of this enzyme possessei substantial peptide character, and so were biologically unstable, poorly absorbed am rapidly metabolised. 

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. 

Richard AM. Structure-based methods for predicting mutagenicity and carcinogenicity are we there yet Mut Res Fund Mol Mech Mut 1998 400 493-507. 

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... 

An analysis of more than 130 preclinical candidates that had attrited during further development showed the failure of the chemotype approach (i.e. that a compound of the same/similar chemotype will have similar risks of attrition and that a structurally diverse chemotype will offer the best approach to minimize attrition risk) and 2D structure-based methods to be able to effectively differentiate compounds [29]. Thus, the risk of failing or succeeding in development is not related to being of the same chemotype , and differentiation by this method may not be the most effective way dangers are both that a valuable series/chemotype could be discarded because of one bad result and that a structurally different compound may actually have similar off-target effects (e.g. due to the decoration versus the scaffold). 

CA s policy for naming acetylenic, acrylic, methacrylic, ethylenic, and vinyl polymers is to use the source-based method, and source-based representation is used to depict the polymers graphically thus, a synonym for polyethylene is polyethylene and not poly(1,2-ethanediyl) a synonym for polypropylene is polypropylene, and poly(vinyl alcohol) is named ethenol homopolymer although ethenol does not exist. Thus, these polymers are named and represented structurally by the source-based method, not the structure-based method. 

Estimation of pv for PCBs Burkhard et al. [8] compared the predictive capability of 11 different methods to estimate pvap for PCBs at 25°C. The comparison includes solely structure-based methods and methods that require the input of Tm, Th, and the entropy of fusion, ASfUS, or a gas-liquid chromatographic retention index. 

If these equations are applied in combination with structure-based methods to estimate Kow, then only Tm or merely the information of liquidity is required as input to 11.4.11 or 11.4.10, respectively. 

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