Chemical spaces virtual exploration

Virtual screening of virtual libraries, or virtual library construction, enables hitherto unknown parts of chemical space to be explored. 

FIGURE 2.2 Exploration of the chemical space includes the classification and analysis of databases. To generate structural models several methodologies have been developed, they can be classified into ligand-based and target-based methods. Models derived from these methods are frequently used as a source for virtual screening. 

A screening library is designed as a maximally diverse subset of the virtual library in order to explore the entire chemical space and to identify compartments of hits or highly potent scaffolds. An increased hit rate is not necessary, and not even expected in this first design step, because the selected set of compounds is evenly distributed in the entire chemical space defined by the virtual library. 

To effectively and efficiently propose the most appropriate molecules for synthesis, two key points should be considered by the project team exploration and exploitation. Exploration uses a molecular diversity measure to efficiently cover the space of virtual molecules with an even distribution of known properties. This leads to a high confidence that the entirety of the space is represented with as few molecules as necessary to demonstrate regions of specific interest This can be achieved using a wide variety of diversity selection algorithms [11]. Here, the question being asked is that of the entirety of the chemical space. 

The assessment of synthetic accessibility (SA) of a lead candidate is a task which plays a role in lead discovery regardless of the method the lead candidate has been identified with. In the case of a de novo designed molecule the experimental validation of its activity requires synthesis of the compound. In the case of experimental or virtual screening exploration of the SAR around the hit, synthetic access to the chemotype is required as well. The more difficult the synthesis of the lead candidate is, the more time and resources are needed for the exploration of this particular area of chemical space. Lead candidates are normally prioritized according to criteria such as drug-likeness [1,2], natural-product likeness [3], predicted activity or freedom to operate with respect to intellectual property. Since sooner or later in the drug discovery process the candidates will be ranked, or even eliminated by their synthetic accessibility, it is desirable to include this aspect into... 

The concepts of molecular similarity (1-3) and molecular diversity (4,5) play important roles in modern approaches to computer-aided molecular design. Molecular similarity provides the simplest, and most widely used, method for virtual screening and underlies the use of clustering methods on chemical databases. Molecular diversity analysis provides a range of tools for exploring the extent to which a set of molecules spans structural space, and underlies many approaches to compound selection and to the design of combinatorial libraries. Many different similarity and diversity methods have been described in the literature, and new methods continue to appear. This raises the question of how one can compare different methods, so as to identify the most appropriate method(s) for some particular application this chapter provides an overview of the ways in which this can be carried out, illustrating such comparisons by,... 

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