Base-line model for identifying the bioaccumulation potential of chemicals

The base-line modeling concept presented in this work is based on the assumption of a maximum bioconcentration factor (BCF) with mitigating factors that reduce the BCF. The maximum bioconcentration potential was described by the multi-compartment partitioning model for passive diffusion. The significance of different mitigating factors associated either with interactions with an organism or bioavailability were investigated. The most important mitigating factor was found to be metabolism. Accordingly, a simulator for fish liver was used in the model, which has been trained to reproduce fish metabolism based on related mammalian metabolic pathways. Other significant mitigating factors, depending on the chemical structure, e.g. molecular size and ionization were also taken into account in the model. The results (r(2)=0.84) obtained for a training set of 511 chemicals demonstrate the usefulness of the BCF base line concept. The predictability of the model was evaluated on the basis of 176 chemicals not used in the model building. The correctness of predictions (abs(logBSF(Obs)-logBCF(Calc))=0.75)) for 59 chemicals included within the model applicability domain was 80%.     

Topological indices for molecular fragments and new graph invariants

Whereas the internal fragment topological index (IFTI) is calculated in the normal manner as for any molecule, the external fragment topological index (EFTI) is calculated so as to reflect the interaction between the excised fragment F and the remainder of the molecule (G-F). For selected topological indices (TIs), a survey of EFTI values, formulas and examples is presented. Some requirements as to the fragment indices are formulated and examined. In the discussion of the results, it is shown that for some TIs regularities exist in the dependence of EFTI values upon the branching of fragment F, or upon the marginal versus central position of the fragment F in the graph G. New vortex invariants can be computed as EFTI values for one-atom fragments over all graph vertices; by iteration, it is in principle possible to devise an infinite number of now vertex invariants.     

Unique description of chemical structures based on hierarchically ordered extended connectivities (HOC procedures). V. New topological indices,ordering of graphs,and recognition of graph similarity

The vertex numbering obtained by application of the HOC algorithm can be converted into two sequences of numbers: If each vertex starting with vertex 1 is only counted once, the sums of numberings of adjacent vertices form sequence S_i (i = 1?N), while the sums of S_i values form sequence M_i (i = 1?N). These two sequences can be used for (i) two new topological indices, ?? and ??, the latter being of extremely low degeneracy, and the former correlating with boiling points of alkanes; (ii) a criterion based on sequence S_i for ordering graphs which possess the same number N of vertices; and (iii) a quantitative measure, also based on sequence S_i, for appreciating the similarity or dissimilarity of pairs of graphs. Comparisons with other topological indices, ordering criteria, and similarity measures for graphs show that the newly devised procedures compare favorably with those known previously.     

Graph—theoretical approach to the calculation of physico-chemical properties of polymers

A topological extrapolation method for the calculation of various properties (melting points, refractive indices, specific rotation, etc.) of infinite linear polymers is developed. The rapid convergence of the oligomer extrapolation series results in very good agreement between calculated and experimental values. Comparison between the proposed method and other empirical or semi-empirical methods (the group addition method and the Pade-approximation) is also presented.     

Reactivity profiles of ligands of mammalian retinoic acid receptors: a preliminary COREPA analysis

Retinoic acid and associated derivatives comprise a class of endogenous hormones that bind to and activate different families of retinoic acid receptors (RARs, RXRs), and control many aspects of vertebrate development. Identification of potential RAR and RXR ligands is of interest both from a pharmaceutical and toxicological perspective. The recently developed COREPA (COmmon REactivity PAttern) algorithm was used to establish reactivity profiles for a limited data set of retinoid receptor ligands in terms of activation of three RARs (alpha, beta, gamma) and an RXR (alpha). Conformational analysis of a training set of retinoids and related analogues in terms of thermodynamic stability of conformers and rotational barriers showed that these chemicals tend to be quite flexible. This flexibility, and the observation that relatively small energy differences between conformers can result in significant variations in electronic structure, highlighted the necessity of considering all energetically reasonable conformers in defining common reactivity profiles. The derived reactivity patterns for three different subclasses of the RAR (alpha, beta, gamma) were similar in terms of their global electrophilicity (nucleophilicity) and steric parameters. However, the profile of active chemicals with respect to interaction with the RXR-alpha differed qualitatively from that of the RARs. Variations in reactivity profiles for the RAR versus RXR families would be consistent with established differences in their affinity for endogenous retinoids, likely reflecting functional differences in the receptors.     

Unique description of chemical structures based on hierarchically ordered extended connectivities (HOC procedures). III. Topological,chemical, and stereochemical coding of molecular structure

A topological code is devised on the basis of the unique topological representation of the molecule described in the preceding two parts of this series.¹ By adding to the topological code additional chemical information on atoms and/or bonds, as well as stereochemical information, a chemical and respectively stereochemical code (SHOC) are also constructed. The advantages of the new linear codes are that they are convention-free codes, preserving the symmetry of molecular graph, and easily implemented either manually or by means of computer programs. By concentrating all topological, chemical, and stereochemical information, our code (SHOC) is more compact and more general than the codes based on several separate lists.     

Comparability graphs and electronic spectra of condensed benzenoid hydrocarbons

A systematic topological approach to the search for regularities in molecular properties has been proposed on the basis of the so-called comparability graphs of isomeric classes of molecules. It is shown that the ordering of the isomeric benzenoid hydrocarbons in the comparability graphs coincides with that of the longest wavelenght in the p band of their electronic spectra.     

Reactivity profiles of ligands of mammalian retinoic acid receptors: A preliminary COREPA analysis

Retinoic acid and associated derivatives comprise a class of endogenous hormones that bind to and activate different families of retinoic acid receptors (RARs, RXRs), and control many aspects of vertebrate development. Identification of potential RAR and RXR ligands is of interest both from a pharmaceutical and toxicological perspective. The recently developed COREPA (COmmon REactivity PAttern) algorithm was used to establish reactivity profiles for a limited data set of retinoid receptor ligands in terms of activation of three RARs ( f , g , n ) and an RXR ( f ). Conformational analysis of a training set of retinoids and related analogues in terms of thermodynamic stability of conformers and rotational barriers showed that these chemicals tend to be quite flexible. This flexibility, and the observation that relatively small energy differences between conformers can result in significant variations in electronic structure, highlighted the necessity of considering all energetically reasonable conformers in defining common reactivity profiles. The derived reactivity patterns for three different subclasses of the RAR ( f , g , n ) were similar in terms of their global electrophilicity (nucleophilicity) and steric parameters. However, the profile of active chemicals with respect to interaction with the RXR- f differed qualitatively from that of the RARs. Variations in reactivity profiles for the RAR versus RXR families would be consistent with established differences in their affinity for endogenous retinoids, likely reflecting functional differences in the receptors.     

Quantitative prediction of biodegradability,metabolite distribution and toxicity of stable metabolites

An evaluation of the capability of organic chemicals to mineralize is an important factor to consider when assessing their fate in the environment. Microbial degradation can convert a toxic chemical into an innocuous one, and vice versa , or alter the toxicity of a chemical. Moreover, primary biodegradation can convert chemicals into stable products that can be difficult to mineralize. In this paper, we present some new results obtained on the basis of a recently developed probabilistic approach to modeling biodegradation based on microbial transformation pathways. The metabolic transformations and their hierarchy were calibrated by making use of the ready biodegradability data from the MITI-I test and expert knowledge for the most probable transformation pathways. A model was developed and integrated into an expert software system named CATABOL that is able to predict the probability of biodegradation of organic chemicals directly from their structure. CATABOL simulates the effects of microbial enzyme systems, generates the most plausible transformation pathways, and quantitatively predicts the persistence and toxicity of the biodegradation products. A subset of 300 organic chemicals were selected from Canada's Domestic Substances List and subjected to CATABOL to compare predicted properties of the parent chemicals with their respective first stable metabolite. The results show that most of the stable metabolites have a lower acute toxicity to fish and a lower bioaccumulation potential compared to the parent chemicals. In contrast, the metabolites appear to be generally more estrogenic than the parent chemicals.     

Unique description of chemical structures based on hierarchically ordered extended connectivities (HOC procedures). VIII. General principles for computer implementation

The computer implementation of the HOC procedures presented in Parts I, II and III of this series is based on the module principle. It contains a main program and seventeen subroutines in Fortran IV. The system is able to provide unique atom numbering and code for all kinds of chemical compounds in their tremendous variety of structures.