China
Africa
Explore chapters and articles related to this topic
Synthetic Endotoxin Antagonists
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Daniel P. Rossignol, Lynn D. Hawkins, William j. Christ, Seiichi Kobayashi, Tsutomu Kawata, Melvyn Lynn, Isao Yamatsu, Yoshito Kishi
Bacterial LPS is a large and complex molecule consisting of a polysaccharide (O-antigen) region, a core region containing, in part, 3-deoxy-D-raafm<9-oct-2-ulo-sonic acid (KDO), and the “lipid A” region (described in more detail below). Lipid A can be derived by acid hydrolysis of LPS and has been identified as the toxicophore of LPS containing the elements necessary for the toxic activity of the entire LPS molecule (31).
Toxicology In Silico
Published in David Woolley, Adam Woolley, Practical Toxicology, 2017
Rule-based SARs use rules generated by experts (generally humans) from literature to determine the toxicity of a structure. These rules try to determine plausible and probable mechanisms and link them to specific structures within the training compounds. If the program detects the presence of a triggering moiety–sometimes termed a toxicophore–in a compound, a structural alert will be triggered. Such structural alerts can be associated with probability (either numerical or nonnumerical) assertions; it is dependent on the user to determine how valid the prediction is to the compound. The method by which these rules are accessed varies from program to program. For instance, some programs, such as ToxTree (developed by Ideaconsult Ltd), use a decision tree–type approach, while others, such as Derek Nexus (developed by Lhasa Ltd), use pattern recognition software to identify potential toxicophores within the structure.
Environmental Androgens and Antiandrogens: An Expanding Chemical Universe
Published in Rajesh K. Naz, Endocrine Disruptors, 2004
L. Earl Gray, Vickie Wilson, Tammy Stoker, Christy Lambright, Johnathan Furr, Nigel Noriega, Phillip Hartig, Mary Cardon, Mitch Rosen, Gerald Ankley, Andrew Hotchkiss, Edward F. Orlando, Louis J. Guillette, William R. Kelce
Although risk assessments are typically conducted on a chemical-by-chemical basis, the 1996 Food Quality Protection Act mandated that the USEPA consider cumulative risk from chemicals that act via a common mechanism. Our studies begin to provide a framework for assessing the cumulative effects of “antiandrogenic” EDCs.5,112 SD rats were dosed orally on days 14 to 18 of gestation with EDCs singly or in pairs at dosage levels equivalent to about 50% the ED50 for hypospadias or epididymal agenesis including (1) two AR antagonists (vinclozolin plus procymidone, each at 50 mg/kg/day), (2) two phthalate esters with a common metabolite (DBP and BBP, each at 500 mg/kg/day), (3) two phthalate esters with different active metabolites (DEHP and DBP (500)), (4) a phthalate ester plus an AR antagonist (DBP [500] plus procymidone [50]), and (5) linuron (75 mg/kg/day) plus BBP (500). We expected that individually each chemical would not induce hypospadias or high levels of other malformations using this dosing regimen, but mixing any two together would induce reproductive tract malformations in about 50% of the males and induce cumulative effects on other androgen-dependent organs. In the current study, all combinations produced cumulative effects on every androgen-dependent tissue. However, only the phthalate ester combinations caused agenesis of the insl3-dependent gubernacular ligaments. The effects of DBP and DEHP in one study and vinclozolin plus procymidone were cumulative, indicating that toxicants need not have a common active metabolite to produce cumulative adverse effects. Rather, these mixtures represent combinations of chemicals with a common “toxicophore” or “pharmacophore.” We also found that EDCs that alter differentiation of the same reproductive tissues during sexual differentiation produce cumulative and apparently dose-additive effects when combined, even if they do not share a common toxicophore, as was the case with the mixture of procymidone plus BBP. It is important to note that the relative potency factors among the chemicals varied from tissue to tissue based upon the mechanism and mode of toxicity. These results indicate that a single toxicity equivalent factor for each chemical will not accurately predict the results of certain mixtures.
Bioactivation of herbal constituents: mechanisms and toxicological relevance
Published in Drug Metabolism Reviews, 2019
Of particular interest is the dual role of some of herb-based substructures in toxicologic and pharmacological activities. A common ‘structural alert’ may act as a toxicophore as well as a pharmacophore. For example, o-quinones bind to proteins and DNA capable of inducing cytotoxic and genotoxic responses and meantime elicits a chemopreventive mechanism via an orchestrated induction of detoxification enzymes. The various biological activities of these reactive metabolites can be seen as a function of their reactivity, selectivity, concentration and duration of exposure, as well as the prooxidant/antioxidant balance in the cells. The multifactorial traits likely contribute to the manifested differences in clinical outcome of herbal remedies with lack of standardization. Future investigations with this focus will assist in clarifying the relationships between chemical reactivities and biological actions, which may be applicable to developing new targeted therapies such as covalent inhibitors (Baillie 2016).
New flavonoid – N,N-dibenzyl(N-methyl)amine hybrids: Multi-target-directed agents for Alzheimer´s disease endowed with neurogenic properties
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Martín Estrada-Valencia, Clara Herrera-Arozamena, Concepción Pérez, Dolores Viña, José A. Morales-García, Ana Pérez-Castillo, Eva Ramos, Alejandro Romero, Erik Laurini, Sabrina Pricl, María Isabel Rodríguez-Franco
With the aim of advancing one step further in the study of the potential therapeutic success of hybrid 6, we performed an in silico prediction of its toxicity and metabolism, using the Derek Nexus system78. The toxicity predictions obtained with Derek Nexus are based on the comparison of the structural features of a given compound with one or more toxicophore patterns (structural alerts) in human species using the Lhasa's knowledge database. Among the 57 toxicity endpoints analysed for hybrid 6, for 56 of them no alerts were predicted at the minimum reasoning level of “impossible” (See Chart S1 in the Supplementary Information). Only in vitro inhibition of the human ether-a-go-go-related gene (hERG) potassium channel was considered “plausible”, although with a low-confidence under 67% according to Judson et al.79
A multiparametric organ toxicity predictor for drug discovery
Published in Toxicology Mechanisms and Methods, 2020
Chirag N. Patel, Sivakumar Prasanth Kumar, Rakesh M. Rawal, Daxesh P. Patel, Frank J. Gonzalez, Himanshu A. Pandya
With advanced improvements of scoring functions in molecular docking as well as close prediction by 3 D-QSAR and pharmacophore/toxicophore approaches, these methods can be unified with chemoinformatic and toxicogenomic techniques into a computational toxicology workflow. It is crucial to define a generalized model in which 3 D computational molecular modeling is used to model the most applicable toxicokinetic, metabolic and molecular toxicological restrictions, thereby facilitating the computational toxicology-driven basis of modern risk assessment while implementing an initiation point for prudent viable molecular design (Piotrowski et al. 2007). Figure 1 shows the schematic view of multiparametric modeling to predict toxicity of different systems.