General library design

Little information is available, and we are in the realm of general library design. 

In general, the described techniques provide an effective, flexible, and relatively fast solution for library design based on analysis of bioscreening data. The quantitative relationships, based on the assessment of contribution values of various molecular descriptors, not only permit the estimation of potential biological activity of candidate compounds before synthesis but also provide information concerning the modification of the structural features necessary for this activity. Usually these techniques are applied in the form of computational filters for constraining the size of virtual combinatorial libraries and... 

Andrews KM, Cramer RD. Toward general methods of targeted library design topomer shape similarity searching with diverse structures as queries. / Med Chem 2000 43 1723-40. 

Baldovi, J. J., Clemente-Juan, J. M., Coronado, E., Gaita-Arino, A. and Gimenez-Saiz, C., (2014) Construction of a General Library for the Rational Design of Nanomagnets and Spin Qubits... 

In general, larger libraries, other than those of Pharmacopeia and Houghten, have tended to be in the range of 5000 to 15000 compounds, particularly if the enhre library was purified and stored as individual compounds. The same methods and algorithms as for diverse library design apply here. However, it now becomes possible... 

Several computational methods require the user to input experimental parameters in order to make predictions. Examples include Yalkowsky s general solvation equation [18], which requires melting points, and Abraham s method [19], which requires five experimentally derived parameters. These methods are not useful for cases before the compounds are synthesized (e.g., in library design or virtual screening), and so they will not be considered further here. 

Even though we have seen that the solubility predictions are poor for individual compounds, there is still a question over whether such predictions could nevertheless be useful in library design. We believe that they can. Figure 15.5 shows that QMPRPIus gets the general trend correct it shows that the proportion of soluble compounds increases with an increase in the solubility predicted by QMPRPIus (where a soluble compound is defined to have intrinsic solubility greater than 10 M). 

In the context of general screening, computational library design involves the selection of a subset of compounds that are optimally diverse and representative of available classes of compounds, leading to a non-redundant chemical library for biological testing. Methods reported in the literature include... 

The methods of simulated annealing (26), genetic algorithms (27), and taboo search (29) are three of the most popular stochastic optimization techniques, inspired by ideas from statistical mechanics, theory of evolutionary biology, and operations research, respectively. They are applicable to our current problem and have been used by researchers for computational library design. Because SA is employed in this chapter, a more-detailed description of the (generalized) SA is given below. 

There are three major sources for a typical corporate compound collection project-specific compounds accumulated over a long period of time through medicinal chemistry efforts for various therapeutic projects, individual compounds from commercial sources, and compounds from combinatorial chemistry. In practice, compound collections are often divided into subsets, for example, the diverse subsets for general HTS and target-focused subsets (such as kinase libraries or GPCR libraries). For library design, diversity and similarity are generally built into the libraries of compounds to be synthesized and/or purchased (73). 

Basic formulation The problem of selecting lead compounds for lead-generation library design can be stated in general as follows Given a distribution ofN compounds, , in a descriptor space L2, find the set of M lead compounds, rh that solves the following... 

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