Diversity simultaneous optimization

Mason, J.S. and Beno, B.R. Library design using BCUT chemistry-space descriptors and multiple four-point pharmacophore fingerprints simultaneous optimization and structure-based diversity. /. Mol. 

Several other approaches with the goal of simultaneous optimization of several criteria have been reported. One such approach is the generation of a library that is both focused and diverse via the dual fingerprint metric described by Bajorath [94], In this method, individual compounds are randomly generated and their similarity to a known inhibitor is evaluated by comparison of their minifingerprints [95] using the Tanimoto coefficient. Those molecules that are above a similarity threshold are then... 

The ability of MoSELEGT to simultaneously optimize molecular weight and diversity was tested in the selection of 30 x 30 combinatorial subsets of a 10000-member virtual amide library. It was shown that as the selection progressed, there was an improvement in both the molecular weight and diversity, as well as a spread of nondominated solutions across the Pareto frontier. The 17 nondominated solutions found after 5000 iterations emphasized the competing nature of these two objectives - those with lower... 

A published synthetic scheme (36) of a four component Ugi reaction (Fig. 6) has been used as an example to demonstrate the use of the SA optimization protocol for the simultaneous optimization of multiple properties. Because two of the four components are fixed in the scheme, only two diversity sites remain for optimization. These two sites come from primary amines (R1NH2) and aldehydes (R2CHO), respectively. We have collected from the ACD (Available Chemical Directory) structures of primary amines and aldehydes available from ALDRICH and LANCASTER. Compounds with reactive or unstable structural patterns are removed. As a result, 779 primary amines and 246 aldehydes are considered. 

Combinatorial library design approaches have been discussed (94), with the design of library subsets that simultaneously optimize the diversity or similarity of a library to a target, properties (such as druglikeness) of the library members, properties (such as cost or availability) of the reactants required to make them, and the efficiency for array synthesis. They showed that libraries can be designed to... 

Beno and Mason [19] describe a product-based method based on simulated annealing that simultaneously optimizes four-point pharmacophore coverage and BCUT diversity. The virtual library is preenumerated however, the four-point pharmacophores are calculated on-the-fly, that is, during the optimization itself. The approach was used to select 20 carboxylic acids and 20 amines from a virtual library of 86,140 amines (292 acids and 295 amines). The library was optimized on pharmacophore coverage simultaneously with diversity in BCUT space. They found a 20-23% increase in BCUT cell coverage and a 1.8- to 2.6-fold increase in the number of pharmacophores covered compared with randomly selected reagents. 

Figure 5 The molecular weight profile of a library optimized on diversity alone (Subset 1) is compared with the profiles found in a library simultaneously optimized on diversity and molecular weight profile (Subset 2) and the World Drugs Index.

Coumarins are pharmacologically active and have been used in the treatment of a diverse range of diseases. The great diversity of coumarin structures and their wide range of polarities present special problems for their simultaneous analysis. The separation of seven closely related coumarins by CZE was studied. Optimized conditions tallied with a 200 mM boric acid—50 mM tetraborate buffer pH 8.5 and were applied to the determination of coumarins in extracts from roots and aerial parts from the plant Chrysanthemum segetum. Baseline separation of six coumarins was achieved in 10 min. 

Fig. 3. A family of libraries (shown by the crosses) is found when optimizing molecular weight profile simultaneously with cell-based diversity when using the MoSELECT program. The single SELECT solution is shown by the solid diamond.

Clearly what is needed in SFC for samples with diverse, wide-ranging compounds is a systematic approach to optimization, applicable when two or more variables are changed simultaneously. The remainder of this chapter is therefore devoted to the description of some systematic, multi-parameter approaches, with a natural emphasis on those strategies for which experimental results are available. 

A recent trend in library design is to optimize libraries over a number of properties simultaneously for example, whether a library is designed to be diverse, focused or some combination of the two, it is desirable that the library is cheap to synthesis and that the compounds contained within the library have drug-like physicochemical properties. Most approaches to multiobjective library design combine the different properties via a weighted-sum fitness function. For example, in the SELECT program the fitness function can have the following form ... 

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