The conventional quantitative-structure-activity relationship (QSAR) provides only a single three-dimensional (3D) model for a given two-dimensional (2D) item in the modeling process. However, in complex reaction environments with solvents of different polarity, especially biological systems, the molecules can take the form of different conformers depending on the particular interaction. Therefore, chemical behavior, e.g. toxicity, may be considered the integral effect of a set of conformers rather than the property of a single 3D isomer. The 'dynamic' QSAR method is unique in that it provided for the calculation of a set of conformers for 2D representation of each chemical of the series under investigation. Moreover, these conformers can be selected interactively according to the hypothesized mechanism of toxic action. The acute lethality of 36 semicarbazides and thiosemicarbazides, evaluated using the Frog Embryo Teratogenesis Assay: Xenopus (FETAX), was modeled by using the 'dynamic' QSAR method. The assumed mode of action, osteolathyrism, was defined by the failure of connective tissue to polymerize properly due to interference with lysyl oxidase. Conformer screenings were based on parameter distribution according to the frontier orbital energies and volume polarizability, conditioning their reactivity and hydrophobicity, respectively. The best results were obtained by the selection of conformers providing prevailing values of electron acceptor properties. Moreover, the best two-parameter QSARs encompassing all the evaluated compounds incorporate a geometric parameter, the geometric analog of the Wiener topological index, and the local electronic characteristics of the C=O or C=S group, superdelocalizabilities and charges.
Available at: http://works.bepress.com/terry_schultz/93/