BackgroundMunicipal drinking water contaminated with perfluorinated alkyl acids had been distributed to one-third of households in Ronneby, Sweden. The source was firefighting foam used in a nearby airfield since the mid-1980s. Clean water was provided from 16 December 2013.ObjectiveTo determine the rates of decline in serum perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), and their corresponding half-lives.MethodsUp to seven blood samples were collected between June 2014 and September 2016 from 106 participants (age 4–84 years, 53% female).ResultsMedian initial serum concentrations were PFHxS, 277 ng/mL (range 12–1660); PFOS, 345 ng/mL (range 24–1500); and PFOA, 18 ng/mL (range 2.4–92). The covariate-adjusted average rates of decrease in serum were PFHxS, 13% per year (95% CI 12% to 15%); PFOS, 20% per year (95% CI 19% to 22%); and PFOA, 26% per year (95% CI 24% to 28%). The observed data are consistent with a first-order elimination model. The mean estimated half-life was 5.3 years (95% CI 4.6 to 6.0) for PFHxS, 3.4 years (95% CI 3.1 to 3.7) for PFOS and 2.7 years (95% CI 2.5 to 2.9) for PFOA. The interindividual variation of half-life was around threefold when comparing the 5th and 95th percentiles. There was a marked sex difference with more rapid elimination in women for PFHxS and PFOS, but only marginally for PFOA.ConclusionsThe estimated half-life for PFHxS was considerably longer than for PFOS and PFOA. For PFHxS and PFOS, the average half-life is shorter than the previously published estimates. For PFOA the half-life is in line with the range of published estimates.
Machine learning algorithms have attained widespread use in assessing the potential toxicities of pharmaceuticals and industrial chemicals because of their faster-speed and lowercost compared to experimental bioassays. Gradient boosting is an effective algorithm that often achieves high predictivity, but historically the relative long computational time limited its applications in predicting large compound libraries or developing in silico predictive models that require frequent retraining. LightGBM, a recent improvement of the gradient boosting algorithm inherited its high predictivity but resolved its scalability and long computational time by adopting leaf-wise tree growth strategy and introducing novel techniques. In this study, we compared the predictive performance and the computational time of LightGBM to deep neural networks, random forests, support vector machines, and XGBoost. All algorithms were rigorously evaluated on publicly available Tox21 and mutagenicity datasets using a Bayesian optimization integrated nested 10-fold cross-validation scheme that performs hyperparameter optimization while examining model generalizability and transferability to new data. The evaluation results demonstrated that LightGBM is an effective and highly scalable algorithm offering the best predictive performance while consuming significantly shorter computational time than the other investigated algorithms across all Tox21 and mutagenicity datasets. We recommend LightGBM for applications in in silico safety assessment and also in other areas of cheminformatics to fulfill the ever-growing demand for accurate and rapid prediction of various toxicity or activity related endpoints of large compound libraries present in the pharmaceutical and chemical industry.
Although computation of binding energies remains a challenging and evolving area, current QM methods can underpin improved docking approaches and offer detailed insights into ligand strain and into the nature and relative strengths of complex active site interactions. The authors envisage that QM will become an increasingly routine and valued tool of the computational medicinal chemist.
Global diversity and activity landscape analysis of endocrine-disrupting chemicals identifies activity cliffs that are rationalized at the structure level.
The identification of new, potent and selective inhibitors of important protein kinase targets is a major goal of drug discovery. Here we analyze the crystal structures of 55 protein kinase complexes with Type II inhibitors and find they adopt a conserved twisted V-shape, with an angle of 121 ± 8° and twist of 78 ± 8°. The tightly conserved twist appears important in ensuring ligands curve around the protein backbone and towards the deep pocket. From this, we develop predictive pharmacophore- and shape-based screens to identify Type II inhibitors from a database which also contains Type I inhibitors as decoys. Both approaches exhibit a good level of discrimination for Type II molecules. The most effective pharmacophore model requires six features and three excluded volume regions. Shape-based screening using ROCS generally performs at least as well as pharmacophore approaches. There is only a moderate dependence of shape-based or pharmacophore-based screens on the underlying conformer generator (MOE, Macromodel, Omega and SPE), as well as on ligand linkage chemistry (amide and urea). Finally, we apply our approach to retrieval of Type II inhibitors from a modified version of the DUD database, containing over 104,000 compounds. We observe good enrichment, providing further evidence that the in silico screens developed here will constitute useful guides for identification of small molecule inhibitors targetting protein kinases in their inactive conformational state.
Endocrine disrupting chemicals (EDCs) from the environment are associated with reproductive abnormalities (i.e. decreased sperm concentration; increased endometriosis) and alterations of the cardiovascular system (i.e. increased blood pressure and risk of coronary disease). Some phthalates esters have been identified as EDCs, for which inhalation is considered as one of the routes of exposure. However, only little is known regarding inhalational exposure to EDCs via urban airborne particles. In the present study, we report the monthly concentration of 8 phthalate esters measured in PM and PM collected and recovered during 7 months in a highly populated area of Mexico City. Using the levels of PM and PM reported by the automatized network of environmental monitoring of Mexico City for the sampling site, we estimated exposure levels for people of different ages and gender. Two endocrine disrupting compounds, the phthalate esters DEHP and DnBP, were found on the particles in higher concentrations during the warmer months of the year. The highest concentration was reported for DEHP (229.7μg/g of particles) in PM collected in May 2013. After calculations of the DEHP concentration in the atmosphere, and using the respiratory flow rate, we determined males were potentially exposed to larger quantities of DEHP, reaching up to 18ng/8h in April 2013. Despite the concentrations of phthalates seem to be rather small, a comprehensive characterization of its presence is necessary in order to evaluate the overall exposure to these compounds, providing a clear view of exposure on children, adolescents and pregnant women.
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