Scaffold identification

Line Notations scaffold identification 1H-lndole12346, then descriptors for 5 randomization points [10R ]1. [10R2]2.[10Rs]3.[10RJ4.[10Rj6, then monomer definitions Me=C, Et=CC, CF2=C(F)(F)F and so on. 

Fig. 6.7 Process of scaffold identification using LEGEND and SEEDS (18).

The molecular scaffolds also provide an unusual opportunity for the identification and recognition of meso structures. For example, successive acylation of L and D phenylalanine with the acridine diacid gives the structure 56 and we anticipate that... 

The use of block copolymers to form a variety of different nanosized periodic patterns continues to be an active area of research. Whether in bulk, thin film, or solution micelle states, block copolymers present seemingly unlimited opportunities for fabricating and patterning nanostructures. The wealth of microstructures and the tunability of structural dimensions make them a favorable choice for scientists in a variety of research fields. As reviewed here, they can function as nano devices themselves, or act as templates or scaffolds for the fabrication of functional nanopatterns composed of almost all types of materials. However, there are still two obvious areas which require more work control of the long-range 3D nanostructure via more user-friendly processes and the identification of new materials with different functional properties. 

Fig. 14 Use of two different DNA duplexes with inserted cytosine loops working as synthetic scaffolds to generate fluorescent silver clusters for the identification of the sickle cell anemia gene mutation (black dots represent hydrogen bonds formed in base pairing and black dashed lines the sugar-phosphate backbone) [74]...

Matrix metalloproteinases (MMPs) are a class of zinc- and calcium-dependent enzymes that are responsible for the metabolism of extracellular matrix proteins [27]. Increased activity of MMPs has been associated with pathological diseases such as arthritis, cancer, multiple sclerosis and Alzheimer s disease [28-31]. Therefore, they constitute an important group of drug targets. Their inhibition is accomplished by blocking the active site of the catalytic domain with ligands that contain hydroxamic or carboxylic acids to chelate the Zn metal. The identification of low molecular weight compounds that contain different scaffolds may lead to the development of a new class of specific inhibitors. 

Fig. 19.10 Flow chart for the NMR identification of novel scaffolds for Zn binding.

J. Couet, S. Li, T. Okamoto, T. Izeku, and M. P. Lisanti. Identification of peptide and protein ligands for the caveolin-scaffolding domain. Implications for the interaction of caveolin with caveolae-associated proteins. J. Biol. Chem. 272 6525-6533... 

Bohl M, Dunbar JB, Gifford EM, Heritage T, Wild DJ, Willett P, Wilton DJ. (2002) Scaffold Searching Automated Identification of Similar Ring Systems for the Design of Combinatorial Libraries. Quant. Struct.-Act. Rel. 21 590-597. 

In a more recent virtual screening study, Ballester et al. reported the successful identification of novel inhibitors of ary-lamine N-acetyltransferascs using the USR algorithm (87). A computational screening of 700 million molecular conformers was conducted very efficiently. A small number of the predicted hits were purchased and experimentally tested. An impressive hit rate of 40% has been achieved. The authors also showed the ability of USR to find biologically active compounds with different chemical structures (i.e., scaffold hopping), evidenced by... 

A second example of protease inhibitor design that properly illustrates the peptide scaffold-based approach is that of thrombin inhibitors. Work with these compounds led to the identification of highly potent, selective, and in vivo-effective lead compounds. A member of the serine protease family, thrombin cleaves a number of substrates (e.g., fibrinogen) and activates its platelet receptor (a G-protein-coupled receptor) by proteolysis of the extracellular N-terminal domain which results in self-activation (for a review see Reference 66). Initial lead inhibitors of thrombin were substrate-based, including the fibrinogen P3-Pi Phe-Pro-Arg sequence [67] and simple Arg derivatives such as Tos-Arg-OMe [68]. 

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