Libraries Structure-Activity Analysis

Combinatorial Peptide and Nonpeptide Libraries A Handbook , VCH, Weinheim, 1996. 

Willett, in A Practical Guide to Combinatorial Chemistry , ed. A. Czamik and S. H. DeWitt, American Chemical Society, Washington, DC, 1997, pp. 17-48. 

HTS = high throughput screen PCA = principal components analysis SAR = structure-activity relationship. 

Each therapeutic class is represented by three to six compounds as a library there is an even representation of 4-8% for each class. The compounds were selected to span the diversity available in known active compounds, and in all cases compounds from different series are represented. One activity class, namely the HIV protease inhibitors, stand out from the perspective of their large size, their general flexibility, and their richness of functionality available for binding interaction. As will be discussed below, these characteristics uncover deficiencies in the methods employed, and thus provide guidance for future improvements in the methodology. 

The validation study has been designed to mimic multiple iterations of the drug design process, where additional information is added to the SAR knowledge base at each iteration. One should anticipate that, as additional SAR information is collected, the efficiency with which a library can be enriched or focused should improve. Moreover, one should also anticipate an increasing level of chemical insight available within the SAR hypotheses, either in the number and nature of the necessary binding interactions, or in the precision with which location and/or directionality of these interactions are known. 

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In view of the inherent complexity of combinatorial libraries, it is not surprising to find a number of EA applications in the field (see Combinatorial Libraries Structure-Activity Analysis). Sheridan and Kearsley describe how a GA can be used to suggest combinatorial library monomers. Each GA individual encodes a possible library compound as a series of monomer bases. The similarity of the encoded compounds to known actives is used as a fitness function. At the end of a GA run good library compounds that resemble known actives are found. 

Combinatorial Chemistry Combinatorial Libraries Structure-Activity Analysis Combinatorics of Small Molecular Structures Competitive Molecular Field Analysis (CoM-FA) Drug Design Molecular Docking and Structure-based Design Quantitative Structure-Activity Relationships in Drug Design Quantitative Structure-Property Relationships (QSPR). 

Recently, Markush structures have also been used to represent combinatorial libraries. The representations and search systems useful for Markush structures in patents are also potentially useful for combinatorial libraries (see Combinatorial Chemistry and Combinatorial Libraries Structure-Activity Analysis). 

Chemical Abstracts Service Information System Combinatorial Chemistry Combinatorial Libraries Structure-Activity Analysis Structural Similarity Measures for Database Searching Structure and Substructure Searching Structure Databases fracture Representation. 

Combinatorial Libraries Structure-Activity Analysis Comparative Molecular Field Analysis (CoMFA)... 

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