Final Library Design

Computer-assisted library design can provide optimized libraries for different applications. In this example, a high overall hit-rate from an unknown library is desirable. A two-step method is used. 

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The remaining library designs are based on applying the MOGA under various constraints. In Fig. 6, the libraries are constrained to contain between 250 and 500 products. Finally, the libraries are constrained to contain between 15 and 20 reactants in each component. The libraries found when no constraint is placed on configuration are shown by the crosses in Fig. 7A, and the libraries found when the constraints are applied are shown by the solid squares. Figure 7B illustrates that the constrained (more efficient) libraries were found without any loss in diversity. 

In this chapter, we will give a brief introduction to the basic concepts of chemoinformatics and their relevance to chemical library design. In Section 2, we will describe chemical representation, molecular data, and molecular data mining in computer we will introduce some of the chemoinformatics concepts such as molecular descriptors, chemical space, dimension reduction, similarity and diversity and we will review the most useful methods and applications of chemoinformatics, the quantitative structure-activity relationship (QSAR), the quantitative structure-property relationship (QSPR), multiobjective optimization, and virtual screening. In Section 3, we will outline some of the elements of library design and connect chemoinformatics tools, such as molecular similarity, molecular diversity, and multiple objective optimizations, with designing optimal libraries. Finally, we will put library design into perspective in Section 4. 

Computational library design process begins with reagent selections, followed by diversity analysis and virtual library enumeration, and ends with selection of a final set of molecular structures to be synthesized (Fig. 9.4). Two databases, Available Chemical Database (ACD) (2) and Chemicals Available for... 

The final library was designed with the purpose of adding incremental diversity to the first three fragment libraries. The main filtering criterion was novel pharmacophoric triangles not found in the first three libraries. After clustering and visual inspection from a panel of medicinal chemists, only 65 compounds were purchased and 61 compounds passed QC. 

The Oriented Substituent Pharmacophore PRopErtY Space (OSPPREYS) approach, introduced by Martin and Hoeffel [6], is in software terms an extension of CCG s MOE package, written using SVL. The 3D oriented substituent pharmacophores are aimed towards better representation of diversity and similarity in combinatorial libraries in the 3D pharmacophore space. Combinatorial library design often operates only on substituents rather than on the final products as the complications related to the conformational coverage in the 3D space and the scaffold dependency limit the product-based approaches to smaller libraries. The 3D oriented substituent pharmacophores add two more points and the corresponding distances to each substituent pharmacophore which represent the relationship of the substituents in the product with only little additional information. The fingerprints permit the creation of property space by multidimensional scaling (MDS) and, since scaffold independent, can be stored separately and applied to different libraries [6],... 

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