Target focus

Protein kinases are important targets in cancer and other diseases. Crystal structures are often available and, thereby, enable structure-based design. However, many ligands target the ATP binding site (i.e., the hinge region) of a kinase, which often results in selectivity ksues. Therefore, novel ATP-competitive libraries are still of interest. 

Researchers at BioFocus described the selectivity ksue by an analysk of the hit rates for 44 compound libraries against up to 17 kinases. Thirty-nine of the libraries showed higher hit rates than a diverse compound set, making it evident 

Due to the large number of available protein structures, kinases still have to be considered the best case for structure-based library design. This is even truer for targeting allosteric modulation [124]. Here, a group of inhibitors has been inden-tified that bind outside the ATP pocket and, thereby, stabilize the DFG motif. 

The most prominent member of these inhibitors is imatinib (Gleevec) [125]. 

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The selection of compounds for an NMR screening library is dictated by its intended purpose. There are four basic types of libraries general screening, targeted, focused, and follow-up. 

More recently, the focus has moved from diversity in favor of combinatorial libraries designed to target specific receptors or enzymes (12). While these single-target-focused libraries remain a key component of many drug-discovery programs, and are useful in both hit to lead and lead optimization contexts,... 

Computational models relating molecular structure and/or properties to biological activity are required for the design of both target-focused and target class combinatorial libraries based on known active ligands. These models are developed from descriptors, which encode information about molecular properties... 

AurSCOPE (Aureus) Collection of target-focused knowledgebases 500 K Selected medicinal chemistry journals Yes... 

There are three major sources for a typical corporate compound collection project-specific compounds accumulated over a long period of time through medicinal chemistry efforts for various therapeutic projects, individual compounds from commercial sources, and compounds from combinatorial chemistry. In practice, compound collections are often divided into subsets, for example, the diverse subsets for general HTS and target-focused subsets (such as kinase libraries or GPCR libraries). For library design, diversity and similarity are generally built into the libraries of compounds to be synthesized and/or purchased (73). 

Since the most favourable chemical fragment space for any given class of targets varies over time, we recommend planning ahead for dynamic library extensions, which may comprise target-focused fragments, new chemistries, new privileged chemical classes or... 

Key Words Chemical diversity compound design diversity-oriented synthesis druglike compounds molecular properties natural products rule of five structure-activity relationship target-focused compound libraries. 

Target focus Biophysical properties Chemistry space... 

In prostate biopsies, immunomarkers that can assist reaching a diagnosis of carcinoma in a small focus of atypical glands are of great utility. The latter has been especially valuable in an organ such as the prostate where a repeat biopsy does not always reach the target focus for additional sampling. The layer of assurance rendered by multiple immunostains used in prostate... 

Its application to the enantiomers of fluorinated allyl alcohols (see scheme 1) would generate optically active allylamines, a substructure of our targets. Focused on Phe-Gly isosteres 3a (R =CH2Ph, = H) the preparation of the corresponding intermediates is shown in scheme 6. 

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