A computerized structure–activity correlation program for relating bacterial mutagenesis activity to chemical structure

Abstract

The program employs a substructure recognition process based on the procedure of Hodes et al. Structural information is accepted from connection tables (Chemical Abstracts Registry I1 or 111) or MCC'-TSS ciphers. Typically in this program the basic substructure unit (ganglion) is an atom triplet. Data for correlation are provided by over 1000 results from mutagenesis tests run in the Ames Salmonella typhimurium test, obtained from the literature. Activity may be calibrated in two to eight levels. Statistical weights for ganglia are calculated from the program of Hodes et al. The results of the program reveal the dependence of biological data on chemical structure, the self-consistency of the data, and the level of activity to be expected of an unknown structure, with an estimate of confidence. The value of the program was shown with 34 unknowns simultaneously tested for activity in the Ames test and submitted to structure-activity analysis. Of these 74% were correctly predicted for the level of activity, and 88% to within one level of activity. It is expected that experience with the program in a trial application setting will enable us to restrict the number of activity calibrations to two. This will allow a simple selection of an inactive or active prediction to be made.

Applications of computers to toxicological research

“…Tinker (43) used a modified Hodes method (an approach based upon atom-centered fragments) to study mutagenesis data (Ames test) for more than 1000 diverse chemicals. The derived model was used to predict the mutagenicity of 34 new compounds not in the original database.…”

“…the Ames test mutagenicity and an electron-withdrawing parameter for 15 organoplatinum compounds. Tinker (43) used a modified Hodes method (an approach based upon atom-centered fragments) to study mutagenesis data (Ames test) for more than 1000 diverse chemicals. The derived model was used to predict the mutagenicity of…”

Substructural QSAR Approaches and Topological Pharmacophores

“…An extended version of this procedure has successfully been applied to mutagenicity data by Tinker as a predictive test for hazard evaluation (43,44). If potentially active compounds are to be selected for a screening program, both the activity as well as the inactivity score have to be taken into account, which can be done in various ways depending on the needs of the selection program.…”

Predicting toxicity through a computer automated structure evaluation program.

“…In more recent developments, though, attempts were made at automating the selection of keys. The work of Chu (14) and Hodes (15,16) are examples of such developments and their programs are clearly related to our own methodology. The problem with these programs was that no causal relationship was established between the substructural descriptors and the activity of the molecules in the data base.…”