Pharmacophore diversity

Davies K. Using pharmacophore diversity to select molecules to test from commercial catalogues. In Chaiken IM and Janda KD, editors. Molecular diversity and combinatorial chemistry. Libraries and drug discovery. Washington DC American Chemical Society, 1996 309-16. 

Makara GM. Measuring molecular similarity and diversity total pharmacophore diversity. J Med Chem 2001 44 3563-71. 

Davies, K. and Briant, C. Combinatorial chemistry library design using pharmacophore diversity. Netw. Sci. 1995, 1. Available at URL http //www.awod.com/netsci/lssues/ July95 /feature6.html. 

The DIVSEL program was developed by Pickett et al. for combinatorial reagent selection using three-point pharmacophores as the descriptor for similarity calculations [2], The algorithm starts by selecting the compound most dissimilar to the others in the set and then iteratively selects compounds most dissimilar to those already selected. DIVSEL was used to select a set of carboxylic acids from a collection of 1100 monocarboxylic acids for an amide library, based on the pharmacophoric diversity of the products. Eleven diverse amines were selected based on pharmacophoric diversity. A virtual library of 12100 amides was constructed from the 11 amines and 1100 carboxylic acids. The DIVSEL program used the pharmacophore fingerprints for the product virtual library to select a diverse set of the carboxylic acids. The products of 90 acids with the 11 amines selected with DIVSEL covered 85% of the three-point pharmacophores represented by the entire 12100 compound virtual library. 

Davies, K. Using Pharmacophore Diversity to Select Molecules to Test from Commercial Catalogues. In Molecular Diversity and Combinatorial Chemistry Libraries and Drug Discovery, Ed. Chaiken, I.M. and K.D. Janda, K.D., 1996, American Chemical Society, Washington DC, pp 309-316. 

Pickett et al. [68] describe a program, DIVSEL, for selecting reactants while taking account of the pharmacophoric diversity that exists in the final products. They describe a 2-component library where the reactants in one pool are fixed and a subset of reactants is to be selected from the second pool. The virtual library is enumerated and a pharmacophore key is generated for each of the product molecules. Reactants are selected from the second pool using a dissimilarity-based compound selection process that represents a candidate reactant by a pharmacophore key that covers an ensemble of products. 

The shared-pool suppliers, as seen in Table 2 below, are capable of providing 70,000-450,000+ compounds each from stock, generally as dry powder/dry film or as solutions in DMSO (from cherry-picked selections or pre-plated sets). The cost of these libraries is relatively low, allowing discovery scientists the opportunity to screen a large number of structurally and pharmacophorically diverse compounds easily and cheaply. By screening a relevant subset from the compounds offered, the user often can use the hits as the basis for structure queries in sourcing analogues for... 

Total Pharmacophore Diversity fingerprints = ToPD fingerprints substructure descriptors (0 pharmacophore-based descriptors)... 

Several product-based approaches to library design that do not require full enumeration have been developed. Pickett et al. have described the design of a diverse amide library where diversity is measured in product space. The DIVSEL program is a DBCS method where dissimilarity is measured in three-point pharmacophore space [83]. Initially, 11 amines were selected based on maximum pharmacophore diversity. Then a total of 1100 carboxylic acids were identified following substructure searching. A set of 1100 pharmacophores keys was generated, where each key corresponds to one acid combined with the 11 amines. DIVSEL was used to select 100 acids based on the diversity of the products. The final library was found to cover 85% of the pharmacophores represented by the entire 12,100 virtual libraries. 

These successes have led to the suggestion that descriptors based on three-point pharmacophores could be useful in assessing the pharmacophoric diversity of large data sets and in library design. The principle is illustrated in... 

As we mentioned before (Section 2.1.10), pharmacophore keys may be derived from a single conformation or an ensemble of conformations. Moreover, pharmacophore maps of more than one structure may be combined into a single plot, a technique that is particularly useful for visualizing and comparing the pharmacophoric diversity of combinatorial libraries. 

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