Chemical scaffolds

After a chemical scaffold tests positive in the IC50 shift assay, it becomes necessary to provide a quantitative measure of the potency and rate of the suspected MBI. ATDI... 

Even with the knowledge of the reactive moieties that are suspected to trigger M BI, there are numerous potential pathways for the chemistry to lead to protein inactivation [174,196]. Differentiating these mechanisms can facilitate the generation of alternate and safer chemical scaffolds. The UV-Vis spectrophotometer has been a key instrument in activity and functional characterization for CYPs for the past 40 years, as indicated by the derivation of its name, pigment 45 0 being the signature UV band present when reduced in the presence of CO [5,197]. This technique has been... 

Protein target families are the fundamentals to build a framework for matching biological motifs with chemical scaffolds. Many structurally related targets find implications in different therapeutic areas, while exhibiting similar protein-ligand... 

In addition to the preceding kinase inhibitors, a number of patents describe compounds that are claimed to be active against PKB (e.g., diamino tri-azines, diaminopyrimidines or 5-aminocarbonylindazoles) [1,144]. Although in general no kinase inhibitory data are provided in these patents, the diverse chemical scaffolds covered in these specifications may represent promising new chemotypes for the future generation of PKB kinase-selective inhibitors. 

Fig. 6.4. Discovery of GGTase-I inhibitors with novel chemical scaffolds using a combination of QSAR modeling and virtual screening.

Define the chemical scaffolds, attachment blocks, linkers, and reaction schemes for the compounds under study. Attachment points on the blocks are represented by [A] , while functional groups to be permutated on the scaffolds are depicted by [R ] , where n is a numerical value unique to each functional group to be varied (Fig. 18.1). Linker is the intersection between the scaffolds and the attachment blocks see Sections 4.3-4.6). 

MCRs are now no longer confined to a few backbones, but hundreds of easily accessible chemical scaffolds have been described and the description of novel scaffolds available through MCRs is a very active area in the organic-chemical literature. Thus MCRs have become very popular in all areas of organic chemistry and especially in applied chemistry, such as the discovery of novel biologically active compounds as drugs or agricultural chemicals, and material sciences. 

The most ancient classification considers whether a certain compound class or chemical scaffold is being formed with success under given reaction conditions -often described by the name of the chemist who discovered or made major contributions to this reactions. Between 700 and 900 such named reactions are known [1]. This classification is mostly product based, but can be connected in certain cases to specific starting materials, e.g. the nitrosamine rearrangement. 

Fig. 10.2. Four different chemical scaffolds available through the Doebner MCR reaction.

Table 7.4 Chemical scaffold-based classification, ligand structures approach to DNA-ligand case study and PDB records of models use d to test the GBPM ... 

In another example of combinatorial parallel chemistry, we have recently used the Ugi three-component reactions (Ugi 3-CR) to construct a library of 16,840 protease inhibitors (25). It has been demonstrated previously that the Ugi-3CR reaction provides a useful chemical scaffold for the design of serine protease inhibitors N-substituted 2-substituted-glycine /V-ary 1/alky 1 -amidcs have been identified that are potent factor Xa, factor Vila, or thrombin inhibitors. The three variable substituents of this scaffold, provided by the amine, aldehyde, and isonitrile starting materials, span a favorable pyramidal pharma-cophoric scaffold that can fill the S1, S2, and S3 pockets of the respective protease. This library was screened against five proteases (factor Xa, trypsin, uro-... 

In most recent developments, it has been possible to devise synthetic strategies whereby a variety of chemical scaffolds can be obtained in one scheme (39). Whereas in former examples of combinatorial synthesis a large number of compounds were synthesized that all shared the same chemical backbone, this new technology is opening new ways toward a diversity that can be used for chemical genomics in a designed strategy (40). 

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