In Silico, in Vitro and in vivo Ecotoxicology and Biodegradability Evaluations of Bioactive Schiff Base Ligand

Bioactive Schiff base ligand, 2-[(1E)-N-{2-[(2-{(Z)-[1-(2 hydroxyphenyl)ethylidene]amino} ethyl)amino]ethyl}ethanimidoyl]phenol was selected for in silico, in vitro and in vivo ecotoxicological and biodegradability studies. In vivo and in vitro ecotoxicological evaluations were estimated by the use of snails (Eobania vermiculata) and microorganisms’ bacteria and fungus respectively. In silico ecotoxicological and biodegradability predictions were carried out online computer software programs such as Pro Tox, Pred-skin, Endocrine Disruptor Knowledge Base (EDKB) and UM-BBD. The obtained results from in vivo bioassays showed moderate toxicity of the ligand at the high concentration (1000 µg/mL) with mortality percent value of 35%. For in vitro evaluations, results showed negative effect against bacteria and fungus. In silico predictions, results showed low toxicity with high LD50 of 4340 mg/kg, no toxic targets and low probability to bind with the majority of endocrine receptors with docking ranging between -7.4 and -8.9. In addition, the results from Human skin sensitization and Murine local lymph node assay indicate sensitizer effect of the ligand. For biodegradability prediction, the results indicate the ability of microorganism to degrade the ligand with no-toxic resultant products. We conclude the possibility to using the ligand without risks from environment and human health.                      

In-Silico Assessments of Fruticulin-A and Demethylfruticulin-A Isolated from Salvia Species Against Important Anticancer Targets

Background and objectives: Bioactive compounds derived from plants have been used to treat various ailments with minimal adverse effects. The in-silico methods are developed to predict the behavior of drug candidates before performing the in-vitro and in-vivo experiments. In the current study, a computational investigation was conducted to understand the probable mechanisms of two benzoquinone diterpenoids namely fruticulin-A and demethylfruticulin-A isolated from several salvia species by molecular docking and dynamic simulation approaches. Methods: The above mentioned compounds with proven anticancer activity were docked against five selected target proteins that regulate cell proliferation and apoptosis including cyclin-dependent protein kinase 2 (CDK-2), CDK-6, DNA topoisomerases I (topo I), topo II and B-cell lymphoma-2 (Bcl-2) using autodock 4.2. Besides, molecular dynamics simulations were applied to evaluate the stability of the best-docked complexes. Results: Both compounds demonstrated remarkable binding affinity to CDK-2 than the known CDK-2 inhibitor. The trajectory analysis for 50 nanosecond (ns) revealed acceptable RMSD, RMSF and Rg values during the entire molecular dynamic simulation which confirmed the stability of complexes. Conclusion: The results of our study displayed that fruticulin-A and demethylfruticulin-A can be developed as excellent natural product derived CDK-2 inhibitors, and further biological experiments should be performed to confirm their use as an efficient option for treating cancer disease

Solubility and ADMET profiles of short oligomers of lactic acid

Polylactic acid (PLA) is a polymer with an increased potential to be used in different medical applications, including tissue engineering and drug-carries. The use of PLA in medical applications implies the evaluation of the human organism\u27s response to the polymer inserting and to its degradation products. Consequently, within this study, we have investigated the solubility and ADMET profiles of the short oligomers (having the molecular weight lower than 3000 Da) resulting in degradation products of PLA. There is a linear decrease of the molar solubility of investigated oligomers with molecular weight. The results that are obtained also reveal that short oligomers of PLA have promising pharmacological profiles and limited toxicological effects on humans. These oligomers are predicted as potential inhibitors of the organic anion transporting peptides OATP1B1 and OATP1B3, they present minor probability to affect the androgen and glucocorticoid receptors, have a weak potential of hepatotoxicity, and may produce eye injuries. These outcomes may be used to guide or to supplement in vitro and/or in vivo toxicity tests such as to enhance the biodegradation properties of the biopolymer.</p

The benefits of in silico modeling to identify possible small-molecule drugs and their off-target interactions

Accepted for publication in a future issue of Future Medicinal Chemistry.The research into the use of small molecules as drugs continues to be a key driver in the development of molecular databases, computer-aided drug design software and collaborative platforms. The evolution of computational approaches is driven by the essential criteria that a drug molecule has to fulfill, from the affinity to targets to minimal side effects while having adequate absorption, distribution, metabolism, and excretion (ADME) properties. A combination of ligand- and structure-based drug development approaches is already used to obtain consensus predictions of small molecule activities and their off-target interactions. Further integration of these methods into easy-to-use workflows informed by systems biology could realize the full potential of available data in the drug discovery and reduce the attrition of drug candidates.Peer reviewe

Prediction of ADME-Tox properties and toxicological endpoints of triazole fungicides used for cereals protection

Within this study we have considered 9 triazole fungicides that are approved to be used in European Union for protecting cereals: cyproconazole, epoxiconazole, flutriafol, metconazole, paclobutrazole, tebuconazole, tetraconazole, triadimenol and triticonazole. We have summarized the few available data that support their effects on humans and used various computational tools to obtain a widely view concerning their possible harmful effects on humans. The results of our predictive study reflect that all triazole fungicides considered in this study reveal good oral bioavailability, are envisaged as being able to penetrate the blood brain barrier and to interact with P-glycoprotein and with hepatic cytochromes. The predictions concerning the toxicological endpoints for the investigated triazole fungicides reveal that they. reflect potential of skin sensitization, of blockage of the hERG K+ channels and of endocrine disruption, that they have not mutagenic potential and their carcinogenic potential is not clear. Epoxiconazole and triadimenol are predicted to have the highest potentials of producing numerous harmful effects on humans and their use should be avoided or limited

Urban Endocrine Disruptors Targeting Breast Cancer Proteins.

Humans are exposed to a huge amount of environmental pollutants called endocrine disrupting chemicals (EDCs). These molecules interfere with the homeostasis of the body, usually through mimicking natural hormones leading to activation or blocking of their receptors. Many of these compounds have been associated with a broad range of diseases including the development or increased susceptibility to breast cancer, the most prevalent cancer in women worldwide, according to the World Health Organization. Thus, this article presents a virtual high-throughput screening (vHTS) to evaluate the affinity of proteins related to breast cancer, such as ESR1, ERBB2, PGR, BCRA1, and SHBG, among others, with EDCs from urban sources. A blind docking strategy was employed to screen each protein-ligand pair in triplicate in AutoDock Vina 2.0, using the computed binding affinities as ranking criteria. The three-dimensional structures were previously obtained from EDCs DataBank and Protein Data Bank, prepared and optimized by SYBYL X-2.0. Some of the chemicals that exhibited the best affinity scores for breast cancer proteins in each category were 1,3,7,8-tetrachlorodibenzo-p-dioxin, bisphenol A derivatives, perfluorooctanesulfonic acid, and benzo(a)pyrene, for catalase, several proteins, sex hormone-binding globulin, and cytochrome P450 1A2, respectively. An experimental validation of this approach was performed with a complex that gave a moderate binding affinity in silico, the sex hormone binding globulin (SHBG), and bisphenol A (BPA) complex. The protein was obtained using DNA recombinant technology and the physical interaction with BPA assessed through spectroscopic techniques. BPA binds on the recombinant SHBG, and this results in an increase of its α helix content. In short, this work shows the potential of several EDCs to bind breast cancer associated proteins as a tool to prioritize compounds to perform in vitro analysis to benefit the regulation or exposure prevention by the general population.This work was supported by Colciencias (567-2012 to D.M-G., 1107-519-29058, 1107-459- 21616), the University of Cartagena (0342010) and the EPSRC. G.J.L.B. is a Royal Society University Research Fellow.This is the author accepted manuscript. The final version is available from ACS via http://dx.doi.org/10.1021/acs.chemrestox.5b0034

Endocrine disrupting potential of replacement flame retardants-Review of current knowledge for nuclear receptors associated with reproductive outcomes

Background and aim: Endocrine disrupting chemicals (EDCs) constitute a major public health concern because they can induce a large spectrum of adverse effects by interfering with the hormonal system. Rapid identification of potential EDCs using in vitro screenings is therefore critical, particularly for chemicals of emerging concerns such as replacement flame retardants (FRs). The review aimed at identifying (1) data gaps and research needs regarding endocrine disrupting (ED) properties of replacement FRs and (2) potential EDCs among these emerging chemicals. Methods: A systematic search was performed from open literature and ToxCast/Tox21 programs, and results from in vitro tests on the activities of 52 replacement FRs towards five hormone nuclear receptors (NRs) associated with reproductive outcomes (estrogen, androgen, glucocorticoid, progesterone, and aryl hydrocarbon receptors) were compiled and organized into tables. Findings were complemented with information from structure-based in silico model predictions and in vivo information when relevant. Results: For the majority of the 52 replacement FRs, experimental in vitro data on activities towards these five NRs were either incomplete (15 FRs) or not found (24 FRs). Within the replacement FRs for which effect data were found, some appeared as candidate EDCs, such as triphenyl phosphate (TPhP) and tris(1,3-dichloropropyl) phosphate (TDCIPP). The search also revealed shared ED profiles. For example, anti-androgenic activity was reported for 19 FRs and predicted for another 21 FRs. Discussion: This comprehensive review points to critical gaps in knowledge on ED potential for many replacement FRs, including chemicals to which the general population is likely exposed. Although this review does not cover all possible characteristics of ED, it allowed the identification of potential EDCs associated with reproductive outcomes, calling for deeper evaluation and possibly future regulation of these chemicals. By identifying shared ED profiles, this work also raises concerns for mixture effects since the population is co-exposed to several FRs and other chemicals

Identifying and Prioritizing Chemicals with Uncertain Burden of Exposure: Opportunities for Biomonitoring and Health-Related Research.

BackgroundThe National Institutes of Health's Environmental influences on Child Health Outcomes (ECHO) initiative aims to understand the impact of environmental factors on childhood disease. Over 40,000 chemicals are approved for commercial use. The challenge is to prioritize chemicals for biomonitoring that may present health risk concerns.ObjectivesOur aim was to prioritize chemicals that may elicit child health effects of interest to ECHO but that have not been biomonitored nationwide and to identify gaps needing additional research.MethodsWe searched databases and the literature for chemicals in environmental media and in consumer products that were potentially toxic. We selected chemicals that were not measured in the National Health and Nutrition Examination Survey. From over 700 chemicals, we chose 155 chemicals and created eight chemical panels. For each chemical, we compiled biomonitoring and toxicity data, U.S. Environmental Protection Agency exposure predictions, and annual production usage. We also applied predictive modeling to estimate toxicity. Using these data, we recommended chemicals either for biomonitoring, to be deferred pending additional data, or as low priority for biomonitoring.ResultsFor the 155 chemicals, 97 were measured in food or water, 67 in air or house dust, and 52 in biospecimens. We found in vivo endocrine, developmental, reproductive, and neurotoxic effects for 61, 74, 47, and 32 chemicals, respectively. Eighty-six had data from high-throughput in vitro assays. Positive results for endocrine, developmental, neurotoxicity, and obesity were observed for 32, 11, 35, and 60 chemicals, respectively. Predictive modeling results suggested 90% are toxicants. Biomarkers were reported for 76 chemicals. Thirty-six were recommended for biomonitoring, 108 deferred pending additional research, and 11 as low priority for biomonitoring.DiscussionThe 108 deferred chemicals included those lacking biomonitoring methods or toxicity data, representing an opportunity for future research. Our evaluation was, in general, limited by the large number of unmeasured or untested chemicals. https://doi.org/10.1289/EHP5133

Chemosphere

Thousands of potential endocrine-disrupting chemicals present difficult regulatory challenges. Endocrine-disrupting chemicals can interfere with several nuclear hormone receptors associated with a variety of adverse health effects. The U.S. Environmental Protection Agency (U.S. EPA) has released its reviews of Tier 1 screening assay results for a set of pesticides in the Endocrine Disruptor Screening Program (EDSP), and recently, the Collaborative Estrogen Receptor Activity Prediction Project (CERAPP) data. In this study, the predictive ability of QSAR and docking approaches is evaluated using these data sets. This study also presents a computational systems biology approach using carbaryl (1-naphthyl methylcarbamate) as a case study. For estrogen receptor and androgen receptor binding predictions, two commercial and two open source QSAR tools were used, as was the publicly available docking tool Endocrine Disruptome. For estrogen receptor binding predictions, the ADMET Predictor, VEGA, and OCHEM models (specificity: 0.88, 0.88, and 0.86, and accuracy: 0.81, 0.84, and 0.88, respectively) were each more reliable than the MetaDrug\u2122 model (specificity 0.81 and accuracy 0.77). For androgen receptor binding predictions, the Endocrine Disruptome and ADMET Predictor models (specificity: 0.94 and 0.8, and accuracy: 0.78 and 0.71, respectively) were more reliable than the MetaDrug\u2122 model (specificity 0.33 and accuracy 0.4). A consensus approach is proposed that reaches general agreement among the models (specificity 0.94 and accuracy 0.89). This study integrates QSAR, docking, and systems biology approaches as a virtual screening tool for use in risk assessment. As such, this systems biology pathways and network analysis approach provides a means to more critically assess the potential effects of endocrine-disrupting chemicals.20172021-01-08T00:00:00ZCC999999/ImCDC/Intramural CDC HHSUnited States/28319747PMC82651621002