Library design procedure

According to the above considerations if the optimization is performed under fixed process parameters the initial step in library design is finished, i.e. the catalysts of the initial library can be introduced into the experimental hologram. However, it is strongly recommended to include one or two process parameters into the library design procedure. Reaction temperature and hydrogen pressure is the two most important process parameters influencing both the activity and the reactivity. 

This rule appeals by its simplicity. All parameters can be easily computed, and therefore the rule is often used in virtual screening and library design procedures. Manifold applications of this rule revealed that compliance to it does not necessarily facilitate distinction between drug-like and... 

Combinatorial library design is a complex procedure that can be divided into several steps as indicated above. A wide variety of different computational tools are available that can be applied to the different steps however, effective use of the tools can require considerable user interaction in order to maximize the chances of finding useful compounds. Thus, the tools should not be considered as black boxes. 

Catalyst library design is considered as an optimization procedure in a multidimensional experimental space. The variables in the multi-dimensional space can be differentiated as follows (i) compositional variables, and (ii) process variables. The term compositional variables have already been discussed. 

Since diversity is a collective property, its precise quantification requires a mathematical description of the distribution of the molecular collection in a chemical space. When a set of molecules are considered to be more diverse than another, the molecules in this set cover more chemical space and/or the molecules distribute more evenly in chemical space. Historically, diversity analysis is closely linked to compound selection and combinatorial library design. In reality, library design is also a selection process, selecting compounds from a virtual library before synthesis. There are three main categories of selection procedures for building a diverse set of compounds cluster-based selection, partition-based selection, and dissimilarity-based selection. 

Resulting fragments are clustered and reclassified into sets of monomers for subsequent library design. The RECAP procedure derives not only suitable chemotypes but also appropriate building blocks for scaffold decoration. Since the monomers are extracted from biologically active compounds, there is a high likelihood that new molecules derived from them will contain biologically important motifs. 

Lobanov and Agrafiotis [84] have developed a similar approach to focused library design where each substitution position is considered in turn. They describe an iterative procedure where, in each iteration, the best substituents at one position are determined whereas the substituents at the other positions are held fixed, with this... 

The library synthetic steps were carefully adjusted to avoid complex purification procedures, but even the simple washing/drying/extraction procedures made this library synthesis rather laborious and time requiring. The authors, in fact, synthesised only 600 discrete compounds of the 3078 which were planned in the library design. This either calls for simpler and effective work-up procedures for multistep solution libraries, which are very difficult to identify, or new automated techniques to overcome the purification/work-up bottleneck (see some of the following paragraphs). 

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