54 research outputs found
Automated Integration of Structural, Biological and Metabolic Similarities to Sustain Read-Across_suppl2
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Identification of structural alerts for liver and kidney toxicity using repeated dose toxicity data
Background: The potential for a compound to cause hepatotoxicity and nephrotoxicity is a matter of extreme interest for human health risk assessment. To assess liver and kidney toxicity, repeated-dose toxicity (RDT) studies are conducted mainly on rodents. However, these tests are expensive, time-consuming and require large numbers of animals. For early toxicity screening, in silico models can be applied, reducing the costs, time and animals used. Among in silico approaches, structure-activity relationship (SAR) methods, based on the identification of chemical substructures (structural alerts, SAs) related to a particular activity (toxicity), are widely employed. Results: We identified and evaluated some SAs related to liver and kidney toxicity, using RDT data on rats taken from the hazard evaluation support system (HESS) database. We considered only SAs that gave the best percentages of true positives (TP). Conclusions: It was not possible to assign an unambiguous mode of action for all the SAs, but a mechanistic explanation is provided for some of them. Such achievements may help in the early identification of liver and renal toxicity of substances
A rational approach to elucidate human monoamine oxidase molecular selectivity
Designing highly selective human monoamine oxidase (hMAO) inhibitors is a challenging goal on the road to a
more effective treatment of depression and anxiety (inhibition of hMAO-A isoform) as well as neurodegenerative
diseases (inhibition of hMAO-B isoform). To uncover the molecular rationale of hMAOs selectivity, two recently
prepared 2H-chromene-2-ones, namely compounds 1 and 2, were herein chosen as molecular probes being highly selective toward hMAO-A and hMAO-B, respectively. We performed molecular dynamics (MD) studies on four
different complexes, cross-simulating one at a time the two hMAO-isoforms (dimer embedded in a lipid bilayer)
with the two considered probes. Our comparative analysis on the obtained 100 ns trajectories discloses a stable
H-bond interaction between 1 and Gln215 as crucial for ligand selectivity toward hMAO-A whereas a water-mediated interaction might explain the observed hMAO-B selectivity of compound 2. Such hypotheses are further
supported by binding free energy calculations carried out applying the molecular mechanics generalized Born
surface area (MM-GBSA) method and allowing us to evaluate the contribution of each residue to the observed
isoform selectivity. Taken as whole, this study represents the first attempt to explain at molecular level hMAO
isoform selectivity and a valuable yardstick for better addressing the design of new and highly selective MAO
inhibitors
A k-NN Algorithm for Predicting Oral Sub-Chronic Toxicity in the Rat
Summary Repeated dose toxicity is of the utmost importance to characterize the toxicological profile o
Structure-Based Design and Optimization of Multitarget-Directed 2H-Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases
The multifactorial nature of Alzheimer’s disease calls for the development of multitarget agents addressing key pathogenic processes. To this end, by following a docking-assisted hybridization strategy, a number of aminocoumarins were designed, prepared, and tested as monoamine oxidases (MAOs) and acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitors. Highly flexible N-benzyl-N-alkyloxy coumarins 2–12 showed good inhibitory activities at MAO-B, AChE, and BChE but low selectivity. More rigid inhibitors, bearing meta- and para-xylyl linkers, displayed good inhibitory activities and high MAO-B selectivity. Compounds 21, 24, 37, and 39, the last two featuring an improved hydrophilic/lipophilic balance, exhibited excellent activity profiles with nanomolar inhibitory potency toward hMAO-B, high hMAO-B over hMAO-A selectivity and submicromolar potency at hAChE. Cell-based assays of BBB permeation, neurotoxicity, and neuroprotection supported the potential of compound 37 as a BBB-permeant neuroprotective agent against H2O2-induced oxidative stress with poor interaction as P-gp substrate and very low cytotoxicity
Persistent photoconductivity in 2-dimensional electron gases at different oxide interfaces
We report on the transport characterization in dark and under light
irradiation of three different interfaces: LaAlO3/SrTiO3, LaGaO3/SrTiO3, and
the novel NdGaO3/SrTiO3 heterostructure. All of them share a perovskite
structure, an insulating nature of the single building blocks, a polar/non-
polar character and a critical thickness of four unit cells for the onset of
conductivity. The interface structure and charge confinement in NdGaO3/SrTiO3
are probed by atomic-scale- resolved electron energy loss spectroscopy showing
that, similarly to LaAlO3/SrTiO3, extra electronic charge confined in a sheet
of about 1.5 nm in thickness is present at the NdGaO3/SrTiO3 interface.
Electric transport measurements performed in dark and under radiation show
remarkable similarities and provide evidence that the persistent perturbation
induced by light is an intrinsic peculiar property of the three investigated
oxide-based polar/non-polar interfaces. Our work sets a framework for
understanding the previous contrasting results found in literature about
photoconductivity in LaAlO3/SrTiO3 and highlights the connection between the
origin of persistent photoconductivity and the origin of conductivity itself.
An improved understanding of the photo- induced metastable electron-hole pairs
might allow to shed a direct light on the complex physics of this system and on
the recently proposed perspectives of oxide interfaces for solar energy
conversion.Comment: 11 pages, 7 figure
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