Cell-Base Diversity Metrics

Cell-base diversity attempts to quantify diversity by dividing chemical space into hyper-rectangular regions and measuring the occupancy of the resulting cells. One advantage of these methods is that, unlike distance-based techniques, they can 

The most intuitive cell-based diversity metric is simply the number of cells occupied by a design defined in (11) where 5, is one if the ith cell is occupied and zero if it is not, M the total number of cells. 

A special case of cell-based methods is a diversity measure proposed for binary fingerprints. Unlike continuous descriptors, binary descriptors such as structural keys and hashed fingerprints can be compared using fast binary operations to give rapid estimates of molecular similarity, diversity, and complementarity. The most common example of a diversity measure applied to binary descriptors is the binary union (inclusive or ). This can be exploited in a number of different ways elegant examples can be found in the following references.  

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Several diversity and space coverage measurements have also been considered in the combinatorial optimization process (15). Diversity and space coverage can be evaluated using a number of cell-based methods. These methods, implemented as diversity metrics (23), evaluate how much of the space occupied by the complete library is filled by the subset. For example, the cell-based fraction metric attempts to select one compound from each cell in order to cover as many cells as possible. However, owing to the combinatorial constraint, the objective to cover all occupied cells can seldom be achieved. The cell-based Chi metric attempts to level out the distribution so as to provide an even allocation of compounds to cells. Cell-based entropy and cell-based density metrics attempt to select more than one compound from the most populated cells, in order to respect the level of occupancy of each cell. The following metrics can be used as target functions in the combinatorial optimization process ... 

A diversity metric is a function to aid the quantification of the diversity of a set of compounds in some predefined chemical space. Diversity metrics fall into three main classes (1) Distance-based methods, which express diversity as a function of the pairwise molecular dissimilarities defined through measurement. (2) Cell-based methods, which define diversity in terms of occupancy of a finite number of cells that represent disjoint regions of chemical space. (3) Variance-based methods, which quantify diversity based on the degree of correlation between a compound s important features. 

In a recent classification study, scaffolds taken from natural products were subjected to a two-step analysis in order to identify a diverse set of natural product scaffolds with preferred ADME-properties." Molecular diversity analysis and selection of natural product scaffolds were carried out using cell-based partitioning and the BCUT metrics." To approximate ADME parameters, rule-of-five " calculations were carried out. A set of about 50 natural product scaffolds fulfilled the desired diversity and ADME criteria. ... 

Cell-based fraction and cell-based density have consistently provided the most satisfactory results in our earlier work (15). The main difference between these two cell-based metrics relates to diversity and representativeness. Whereas cell-based fraction is designed to sample the complete library with... 

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