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G Klopman

Publications and source records attributed to G Klopman.

At least 19 recordsLinked to original sources
PubMed1992

Structure-activity study and design of multidrug-resistant reversal compounds by a computer automated structure evaluation methodology.

We have studied the relation between the structure and the multidrug resistance-reversal activity of a set of diverse chemicals with the MULTICASE structure-activity program. A number of key structural features were identified as being related to multidrug resistance reversal activity. Using these key features, we identified seven new compounds predicted to have substantial activity. These were obtained and tested experimentally on a CHO/CHRC5 cell line derived from the AB1 Chinese hamster ovary line in the presence of vincristine and vinblastine. Of the seven compounds tested so far, four showed substantial reversal activity, the most potent of them exhibiting activity at par with verapamil.

Animals↗
PubMed1992

Structural requirements for the induction of the SOS repair in bacteria by nitrated polycyclic aromatic hydrocarbons and related chemicals.

The CASE (computer-automated structure evaluation) methodology was used to investigate the structural basis of the SOS-inducing activity of 56 nitrated polycyclic aromatic hydrocarbons (nitroarenes, nPAH) and the unsubstituted parent PAH molecules. Based upon the presence and/or absence of structural features, CASE identified 5 activating (biophores) and 4 inactivating (biophobes) fragments responsible for the SOS-inducing activity. Based upon these fragments, CASE correctly calculated the genotoxicity of 94.6% of the molecules in the training set (sensitivity = 0.85, specificity = 1.0). Disregarding the questionable experimental results of the unexpected very weak direct-acting activity of the unsubstituted benzo[a]pyrene, dibenzo[a,h]anthracene and 7,12-dimethylbenz[a]anthracene, the concordance of the prediction was 100%, i.e., sensitivity = 1.0, specificity = 1.0. Additionally, the quantitative analysis of the SOS-inducing potency showed a good correlation between the experimental and predicted results. The present analyses indicate an identity in the structural determinants responsible for SOS induction in E. coli PQ37 (SOS chromotest) and mutagenicity in Salmonella typhimurium.

Computer Simulation↗
PubMed1992

Testing by artificial intelligence: computational alternatives to the determination of mutagenicity.

In order to develop methods for evaluating the predictive performance of computer-driven structure-activity methods (SAR) as well as to determine the limits of predictivity, we investigated the behavior of two Salmonella mutagenicity data bases: (a) a subset from the Genetox Program and (b) one from the U.S. National Toxicology Program (NTP). For molecules common to the two data bases, the experimental concordance was 76% when "marginals" were included and 81% when they were excluded. Three SAR methods were evaluated: CASE, MULTICASE and CASE/Graph Indices (CASE/GI). The programs "learned" the Genetox data base and used it to predict NTP molecules that were not present in the Genetox compilation. The concordances were 72, 80 and 47% respectively. Obviously, the MULTICASE version is superior and approaches the 85% interlaboratory variability observed for the Salmonella mutagenicity assays when the latter was carried out under carefully controlled conditions.

Artificial Intelligence↗
PubMed1992

Structural basis of the in vivo induction of micronuclei.

The structural basis of the in vivo induction of micronuclei was examined with CASE, a structure-activity relational method. The CASE program identified a number of structures associated with this activity. When used to predict the activity of chemicals not included in the learning set, these structural determinants gave a concordance in excess of 83%. The existence of a structural basis for the induction of micronuclei will permit an investigation of the mechanistic basis of this phenomenon.

Databases, Factual↗
PubMed1992

1,4-Dioxane: prediction of in vivo clastogenicity.

1,4-Dioxane was analyzed with the CASE program to determine the structural basis of its potential genotoxicity and carcinogenicity. These investigations led to the prediction that while 1,4-dioxane was not genotoxic in vitro, it was an inducer of micronuclei in the bone marrow of rats and a carcinogen for both rats and mice. If it is assumed that the induction of micronuclei is the result of DNA damage, then this potential and the previous report of the in vivo induction of DNA strand breaks in rat liver raise the possibility of a genotoxic action for 1,4-dioxane. However it is also conceivable that we have identified a structural feature which contributes to the induction of micronuclei by a non-genotoxic mechanism.

Animals↗
PubMed1992

Decreased electrophilicity of chemicals carcinogenic only at the maximum tolerated dose.

While there was no significant difference between the actual or predicted mutagenicity and clastogenicity of a group of chemicals carcinogenic only at the maximum tolerated dose (MTD) and a group of chemicals carcinogenic below the MTD, as a group, the chemicals carcinogenic below the MTD exhibited a significantly decreased LUMO (Lowest Unoccupied Molecular Orbital) energy, indicative of increased electrophilicity (i.e. DNA reactivity). These findings suggest that chemicals carcinogenic only at the MTD either require increased doses of "weak" electrophiles to be carcinogenic or that they may act by a "non-genotoxic" mechanism.

Animals↗
PubMed1992

A structural analysis of the genotoxic and carcinogenic potentials of cyclosporin A.

The structural determinants identified by CASE, a knowledge-based structure--activity relational expert system, as contributing to toxicological effects have been distilled from the informational content of over 2000 molecules that have been adequately tested. This methodology has been applied to an analysis of the potential structural determinants of the mutagenicity, clastogenicity and carcinogenicity of cyclosporin A. The analysis predicts that cyclosporin A is devoid of mutagenicity, clastogenicity and DNA-modifying activity. There is however, a structural basis for its carcinogenicity in rodents, i.e. it appears to be a 'non-genotoxic' carcinogen. As a group, 'non-genotoxic' carcinogens are considered by some to pose a far lesser risk to humans than 'genotoxic' ones. The analysis is consistent with the interpretation that the carcinogenicity and immunosuppressive properties of cyclosporin A derive from different mechanisms and are, therefore, separable.

Animals↗
PubMed1992

Structural basis of the genotoxicity of polycyclic aromatic hydrocarbons.

The Computer Automated Structure Evaluation (CASE) system has been applied to investigate the structural basis of the genotoxicity of 37 polycyclic aromatic hydrocarbons examined with the Escherichia coli PQ37 genotoxicity assay (SOS chromotest). CASE identified eight activating and one inactivating structural fragments responsible, for the probability and three activating and one inactivating fragment responsible for the potency of the activity (P less than or equal to 0.15). The present analysis indicate that the main activating fragments identified by CASE were similar to the descriptor for the bay (or modified bay) and K region of PAHs. Using these fragments the computer correctly predicted the probability of genotoxicity of 93.6% of the known genotoxicants and nongenotoxicants in the database. Moreover, the concordance between prediction and experimental results for molecules not in the learning set is greater than 78%.

Animals↗
PubMed1991

Use of artificial intelligence in structure-affinity correlations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) receptor ligands.

The Computer-Automated Structure Evaluation (CASE) Program, an expert system that automatically selects relevant descriptors for structure-activity relationships, has been used to analyze the binding of various ligands to the tetrachloro-dibenzo-p-dioxin (TCDD) receptor or Ah receptor. Two databases were analyzed. One database contained 136 polycyclic aromatic hydrocarbons (PAH), substituted dibenzo-p-dioxins, dibenzofurans and biphenyls whose binding affinities were measured by a sucrose density gradient technique. The other 87 compound database contained PAH, nitro-PAH, halo-PAH and N-heterocycles. Their binding affinities were measured by the electrofocusing assay. Within each training set significant correlations between the affinity for the TCDD receptor and relevant molecular fragments identified by the CASE program were observed. Among the halogenated aromatic hydrocarbons, fragments containing lateral halogens and a longitudinal hydrogen appeared important for TCDD receptor binding. The fragments of PAH and heterocyclic compounds that were most activating with respect to TCDD receptor binding were found to contain the classical 'bay' region and were in fact identical to the fragments found previously to be related to carcinogenicity. It was found that the activating fragments from PAH and heterocyclic compounds were different from those found within the halogenated compounds such as dibenzo-p-dioxins, dibenzofurans and biphenyls. One interpretation of the data is that two different recognition sites may be involved in Ah receptor binding.

Artificial Intelligence↗
PubMed1991

Omeprazole: an exploration of its reported genotoxicity.

Because of its reported ability to induce unscheduled DNA synthesis in the gastric mucosa, the safety of omeprazole, a potentially clinically useful anti-ulcer drug, has been the subject of debate. We have undertaken a detailed computer-based study of structural basis of the putative mutagenicity, genotoxicity and carcinogenicity in rodents of omeprazole and of its sulphenimide, and we conclude that omeprazole is a potential 'genotoxic' carcinogen. The analysis is consistent with the possibility that these activities are associated with the unstable sulphenimide metabolite.

Animals↗
PubMed1991

Structure-activity relations: maximizing the usefulness of mutagenicity and carcinogenicity databases.

The most important criteria for the development and analysis of databases for elucidating the structural bases of toxicological activity include the integrity of the databases with respect to uniformity of the experimental protocol and interpretation of the test results and inclusion of chemicals representing different chemical classes and differing mechanisms of action. Within these criteria, it is demonstrated that when the chemicals are chosen at random, the larger the database, the better the predictivity of chemicals not included in the learning set. It is shown however, that when chemicals are selected on the basis of structural features, that a learning set of approximately 180 chemicals is as informative as a database consisting of 800 chemicals chosen at random.

Animals↗
PubMed1990

The carcinogenic potential of cocaine.

Analysis of cocaine by CASE, an expert system, results in the prediction that cocaine is a rodent carcinogen. In view of the widespread exposure to cocaine this is cause for alarm, especially as in utero exposure has been widely documented and the developing human fetus is at an increased risk of transplacental cancer induction.

Animals↗
PubMed1990

Significant differences in the structural basis of the induction of sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells.

The structural basis of the induction of sister chromatid exchanges (SCE) and chromosomal aberrations (Cvt) in Chinese hamster ovary cells was investigated by the CASE (Computer Automated Structure Evaluation) method, an artificial-intelligence-based system. Using the relevant National Toxicology Program data bases CASE identified a set of structural determinants responsible for the induction of SCE and another one for Cvt. A comparison between the structural determinants associated with SCE and Cvt revealed an overlap of only 22.6%, while the overlap between SCE and the determinants of mutagenicity in Salmonella is 54.5%. This indicates a) that the structural bases of the two phenomena differ and b) that it is likely that SCE, but not Cvt, involves a significant electrophilic/DNA-damaging component.

Animals↗
PubMed1990

New structural concepts for predicting carcinogenicity in rodents: an artificial intelligence approach.

The Computer Automated Structure Evaluation (CASE) method for studying structure-activity relationships has been applied to a data base of rodent carcinogens. It has been demonstrated that CASE is able to identify determinants embedded in the molecular structure which, with a high probability, predict rodent carcinogenicity. CASE has also identified determinants associated with the activity of non-genotoxic carcinogens, thereby suggesting that there is a structural commonality in the activity of these molecules. The present study reveals that there are "universal" as well as species-specific structural determinants of carcinogenicity. CASE was able to predict the carcinogenicity in rodents of certain endogenous pesticides in edible plants.

Animals↗
PubMed1990

Computer Automated Structure Evaluation (CASE) of the teratogenicity of retinoids with the aid of a novel geometry index.

The CASE (Computer Automated Structure Evaluation) program, with the aid of a geometry index for discriminating cis and trans isomers, has been used to study a set of retinoids tested for teratogenicity in hamsters. CASE identified 8 fragments, the most important representing the non-polar terminus of a retinoid with an additional ring system which introduces some rigidity in the side chain. The geometry index helped to identify relevant fragments with an all-trans configuration and to distinguish them from irrelevant fragments with other configurations.

Abnormalities, Drug-Induced↗