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Combinatorial × Computational × Cheminformatics (C3) Approach to Characterization of Congeneric Libraries of Organic Pollutants

Congeners are molecules based on the same carbon skeleton but are different by the number of substituents and/or a substitution pattern. Examples are 1-chloronaphthalene, 1,4-dichloronaphthalene, and 1,3,8-trichloronaphthalene. Various persistent organic pollutants (POPs) exist in the environment as families of congeners. Very large numbers of possible congeners make their experimental characterization and risk assessment unfeasible. Computational high-throughput and quantitative structure-property relationship (QSPR) modeling has been limited by the lack of tools and approaches facilitating analysis of such POP families. We present a comprehensive approach that enables modeling of extremely large congeneric libraries. The approach involves three steps: (1) combinatorial generation of a library of congeners, (2) quantum chemical characterization of each structure at the PM6 semiempirical level to obtain molecular descriptors, and (3) analysis of the information generated in step 2. In steps 1-3, we employ combinatorial, computational, and cheminformatics techniques, respectively. Therefore, this hybrid approach is named "Combinatorial × Computational × Cheminformatics", or just abbreviated as C(3) (or C-cubed) approach. We demonstrate the usefulness of this approach by generating and characterizing Br- and Cl-substituted congeneric families of 23 typical POPs. The analysis of the resulting set of 1 840 951 congeners that includes Cl-, Br-, and mixed Br/Cl-substituted species, proves that, based on structural similarities defined by the molecular descriptors' values, the existing QSPR models developed originally for Cl- and Br-substituted congeners can be applied also to mixed Br/Cl-substituted ones. Thus, the C(3) approach may serve as a tool for exploring structural applicability domains of the existing QSPR models for congeneric sets.