Library molecules

Ugi, L, Werner, B., Domling, A. (2003) The Chemistry of Isocyanides, Their Multi-Component Reactions and Their Libraries. Molecules, 8, 53-66. 

This process refers to libraries where codes and library components are the same, but a clear distinction between coding molecules and library molecules can be made. Theoretically any one bead-one compound [7] library could be fully processed by bioanalytical methods [4] but the compounds must be cleaved off the beads, aliquoted and sent sequentially to the biological test and to structure determination for the test positives. Problems such as the stability of the components stored in solution, their concentration after prolonged storage, their solubility in the medium, and so on could arise from the total release in solution of the compounds. Partial controlled release of the library components in solution (library structures), their biological evaluation, and eventually their structure determination from the resin bound portion (coding structures) on positive beads makes a reliable process and has been the focus of published works, which will be presented in this section. 

The combinatorial docking tools PRO SELECT [121] and CombiDOCK [122] are based on the incremental construction method. In both approaches, a library is formed by a template (or core) molecule with a set of attachment points to which one out of a predefined set of substituents can be connected. The template is then positioned in the active site without considering the substituents. Starting from a few orientations of the template, the substituents are placed into the active site of the protein independently. In case of PRO SELECT, substituents are then selected based on score and additional criteria like 2D similarity and feasibility of synthesis. CombiDOCK calculates a final score for whole library molecules by combining fragment scores. 

This is exemplified on the directly measured library PYL-1 (Fig. 17.10), where the signals of the compounds Py-6 and Py-16 are absent, presumably due to poor ionization yields. Also, compounds Py-13 and Py-17 have the same nominal molecular mass and therefore cannot be differentiated by MS. The fragmentations [M + H-17]+ and [M + H-43]+ of the library molecules lead to a multiplicity of signals complicating the transparency of the mass spectrum. As an example, the signal at m/z 249 can be assigned either to compound... 

In this chapter, we will first discuss the basic principles of DNA-templated organic synthesis, as it is the mechanistic foundations for DNA-encoded libraries then we will discuss the progressive development of DNA-templated libraries and the evolution into a novel drug discovery tool. We will also discuss the DNA-recorded library, which also encodes library molecules with DNA but is conceptually different. These discussions will naturally involve specific drug discovery programs in which these libraries were applied and finally, we will discuss the outlook of DNA-eneoded libraries in the future of drug discovery. 

Georgieva Y, Konthur Z (2011) Design and screening of Ml3 phage display cDNA libraries. Molecules 16(2) 1667-1681. doi 10.3390/moleculesl6021667... 

Ugi I, Werner B, Domling A. The Chemistry of Isocyanides, their MultiComponent Reactions and their Libraries. Molecules 2003 8 53-66. 

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