Library Design via Computational Tools

The use of computational tools to increase the quality of combinatorial libraries is becoming more and more popular. These methods can be applied to any library format, and their careful use may add significant value to the library. Their main apphcation is the selection of individuals/monomers for a library from the many virtual mono-mers/final compounds theoretically available by using all the easily accessible monomers. We will examine in detail the usefulness of computational tools for each library format through the presentation of the main reported approaches by leading groups in 

Primary libraries are not inspired by any strucmral information, and their purpose is to contain the maximum of chemical diversity so as to function as a potential source of active compounds for many different applications. To consider a library size and its diversity as directly proportional entities is totally wrong, as the simple example in Fig. 5.8 shows. The library on the left, composed of 25 molecules, is much more diverse than the 50-member library on the right because it spans more of the chemical space reported in the figure. While the concept of chemical diversity is intuitive, in order to measure the diversity of library components and to select from them the most representative, we must define some key features and methods. 

If we consider the example of Fig. 5.10, when the reagents are selected to produce a20x lOx 10 = 2000-membered library we end up with combined monomer sets composed of 40, rather than 3500, individuals (Fig. 5.11, top). If the 2000 most diverse library components are selected from the product space (Fig. 5.11, bottom), it may be that a significant fraction, or even all, the virtual monomers from one set must be used to prepare them, so that the library cost, in terms of both reagents and human effort, is not significantly reduced. This selection problem was noticed (31) during the selection from a virtual library of the 1600 most diverse amides, which were found to contain 137 amine and 146 carboxylic acid building blocks (19,992 possible combi- 

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. 

Monomer selection may be significantly assisted by a different perspective, that is the computational evaluation of the reaetivity of each potential monomer belonging to a virtual set. In fact, it may well happen that a suitable, diversity-adding selected monomer has a poor reaetivity in the hbrary reaction scheme that will eventually 

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