A categorical structure-activity relationship analysis of GPR119 ligands.

The categorical structure-activity relationship (cat-SAR) expert system has been successfully used in the analysis of chemical compounds that cause toxicity. Herein we describe the use of this fragment-based approach to model ligands for the G protein-coupled receptor 119 (GPR119). Using compounds that are known GPR119 agonists and compounds that we have confirmed experimentally that are not GPR119 agonists, four distinct cat-SAR models were developed.

Evaluation of in silico models for the identification of respiratory sensitizers.

Low molecular weight (LMW) respiratory sensitizers can cause occupational asthma but due to a lack of adequate test methods, prospective identification of respiratory sensitizers is currently not possible. This article presents the evaluation of structure-activity relationship (SAR) models as potential methods to prospectively conclude on the sensitization potential of LMW chemicals. The predictive performance of the SARs calculated from their training sets was compared to their performance on a dataset of newly identified respiratory sensitizers and nonsensitizers, derived from literature.

Global structure-activity relationship model for nonmutagenic carcinogens using virtual ligand-protein interactions as model descriptors.

Structure-activity relationship (SAR) models are powerful tools to investigate the mechanisms of action of chemical carcinogens and to predict the potential carcinogenicity of untested compounds. We describe the use of a traditional fragment-based SAR approach along with a new virtual ligand-protein interaction-based approach for modeling of nonmutagenic carcinogens. The ligand-based SAR models used descriptors derived from computationally calculated ligand-binding affinities for learning set agents to 5495 proteins.

Anticancer SAR models for MCF-7 and MDA-MB-231 breast cell lines.

The National Cancer Institute's Developmental Therapeutics Program (DTP) maintains the screening results obtained in 60 standardized cancer cell lines for ~43,000 compounds. Here the application of the categorical structure-activity relationship (cat-SAR) program for the identification of the structural attributes of identified compounds that display differential cytostatic or cytotoxic activity to one breast cancer cell line and not another is reported. The goal of this approach is to separate features associated with antiproliferative activity towards many cell lines from those that affect only a specific cell type.

Anacardic acid inhibits estrogen receptor alpha-DNA binding and reduces target gene transcription and breast cancer cell proliferation.

Anacardic acid (AnAc; 2-hydroxy-6-alkylbenzoic acid) is a dietary and medicinal phytochemical with established anticancer activity in cell and animal models. The mechanisms by which AnAc inhibits cancer cell proliferation remain undefined. AnAc 24:1(omega5) was purified from geranium (Pelargonium x hortorum) and shown to inhibit the proliferation of estrogen receptor alpha (ERalpha)-positive MCF-7 and endocrine-resistant LCC9 and LY2 breast cancer cells with greater efficacy than ERalpha-negative primary human breast epithelial cells, MCF-10A normal breast epithelial cells, and MDA-MB-231 basal-like breast cancer cells.

A categorical structure-activity relationship analysis of the developmental toxicity of antithyroid drugs.

The choice of therapeutic strategies for hyperthyroidism during pregnancy is limited. Surgery and radioiodine are typically avoided, leaving propylthiouracil and methimazole in the US. Carbimazole, a metabolic precursor of methimazole, is available in some countries outside of the US.

Structure-activity relationship analysis of rat mammary carcinogens.

Structure-activity relationship (SAR) models are powerful tools to investigate the mechanisms of action of chemical carcinogens and to predict the potential carcinogenicity of untested compounds. We describe here the application of the cat-SAR (categorical-SAR) program to two learning sets of rat mammary carcinogens. One set of developed models was based on a comparison of rat mammary carcinogens to rat noncarcinogens (MC-NC), and the second set compared rat mammary carcinogens to rat nonmammary carcinogens (MC-NMC).

The challenge of testing chemicals for potential carcinogenicity using multiple short-term assays: an analysis of a proposed test battery for hair dyes.

Recent reports of the association of hair dyes usage with increased bladder cancer risk in women with the slow NAT-2 acetylator phenotype have resulted both in attempts to identify the putative carcinogen as well as in devising batteries of tests that could be used to screen for such putative carcinogens in hair dye formulations, their intermediates and final products. Analytical studies have reported the presence of traces ( approximately 0.5 ppm) of the carcinogen 4-aminobiphenyl in some hair dye preparations.

Lack of predictivity of the rat lethality (LD50) test for ecological and human health effects.

The relationship between acute toxicity in rats (LD50 values) and indicators of potential health hazards in humans was investigated, based on a chemical population-based paradigm (i.e. the "chemical diversity approach").

CoMFA, HQSAR and molecular docking studies of butitaxel analogues with beta-tubulin.

Results from biochemical analyses for a series of 20 butitaxel analogues, paclitaxel and docetaxel were used to build two- and three-dimensional quantitative structure-activity relationship (QSAR) models in order to investigate the properties associated with microtubule assembly and stabilization. A comparative molecular field analysis (CoMFA) model was built using steric and electrostatic fields. The CoMFA model yielded an r2 of 0.

Identification of structural components associated with cytostatic activity in MCF-7 but not in MDA-MB-231 cells.

The National Cancer Institute's Developmental Therapeutics Program maintains the screening results obtained in 60 standardized cancer cell lines and contained 37,836 compounds for this study. This dataset has shown to be an outstanding resource for the development of structure-activity relationship (SAR) models describing anticancer activity. We report here a novel SAR modeling approach based on a subtractive protocol to develop models that describe cell type-specific molecular descriptors of cytotoxicity.

Validity of methods to predict the respiratory sensitizing potential of chemicals: A study with a piperidinyl chlorotriazine derivative that caused an outbreak of occupational asthma.

A piperidinyl chlorotriazine (PCT) derivative, used as a plastic UV-stabilizer, caused an outbreak of occupational asthma. We verified, in BALB/c mice, the sensitizing potential of PCT in comparison to a known respiratory sensitizer (toluene diisocyanate [TDI]) and a known dermal sensitizer (oxazolone), using three different methods in order to evaluate the validity of current models of sensitization. These included the local lymph node assay (LLNA) and the mouse IgE test.

Environmental odors and health hazards.

Using the recently developed and validated 'chemical diversity approach', the potential of chemicals, to be detected by the human olfactory system and to cause adverse health effects, was investigated. The analyses found no significant association between odor perceptibility and potential for inducing health effects.

Environmental persistence of chemicals and their carcinogenic risks to humans.

A "chemical population"-based investigation of xenobiotics (i.e. a sample of 10,000 chemicals representative of agents in commerce, industry, and the environment, both synthetic and natural) that have the potential for ecotoxicity because of their persistence in the environment and their potential association with carcinogenic risks to humans was undertaken.