Predicting Cytotoxicity of Metal Oxide Nanoparticles using Isalos Analytics Platform.

A literature curated dataset containing 24 distinct metal oxide (MexOy) nanoparticles (NPs), including 15 physicochemical, structural and assay-related descriptors, was enriched with 62 atomistic computational descriptors and exploited to produce a robust and validated in silico model for prediction of NP cytotoxicity. The model can be used to predict the cytotoxicity (cell viability) of MexOy NPs based on the colorimetric lactate dehydrogenase (LDH) assay and the luminometric adenosine triphosphate (ATP) assay, both of which quantify irreversible cell membrane damage. Out of the 77 total descriptors used, 7 were identified as being significant for induction of cytotoxicity by MexOy NPs. These were NP core size, hydrodynamic size, assay type, exposure dose, the energy of the MexOy conduction band (EC), the coordination number of the metal atoms on the NP surface (Avg. C.N. Me atoms surface) and the average force vector surface normal component of all metal atoms (v⟂ Me atoms surface). The significance and effect of these descriptors is discussed to demonstrate their direct correlation with cytotoxicity. The produced model has been made publicly available by the Horizon 2020 (H2020) NanoSolveIT project and will be added to the project's Integrated Approach to Testing and Assessment (IATA).

Fe-Doped ZnO nanoparticle toxicity: assessment by a new generation of nanodescriptors.

In the search for novel tools to combat cancer, nanoparticles (NPs) have attracted a lot of attention. Recently, the controlled release of cancer-cell-killing metal ions from doped NPs has shown promise, but fine tuning of dissolution kinetics is required to ensure specificity and minimize undesirable toxic side-effects. Theoretical tools to help in reaching a proper understanding and finally be able to control the dissolution kinetics by NP design have not been available until now. Here, we present a novel set of true nanodescriptors to analyze the charge distribution, the effect of doping and surface coating of whole metal oxide NP structures. The polarizable model of oxygen atoms enables light to be shed on the charge distribution on the NP surface, allowing the in detail study of the factors influencing the release of metal ions from NPs. The descriptors and their capabilities are demonstrated on a Fe-doped ZnO nanoparticle system, a system with practical outlook and available experimental data.

In Silico Design of Optimal Dissolution Kinetics of Fe-Doped ZnO Nanoparticles Results in Cancer-Specific Toxicity in a Preclinical Rodent Model.

Cancer cells have unique but widely varying characteristics that have proven them difficult to be treated by classical therapeutics and calls for novel and selective treatment options. Nanomaterials (NMs) have been shown to display biological effects as a function of their chemical composition, and the extent and exact nature of these effects can vary between different biological environments. Here, ZnO NMs are doped with increasing levels of Fe, which allows to finely tune their dissolution rate resulting in significant differences in their biological behavior on cancer or normal cells. Based on in silico analysis, 2% Fe-doped ZnO NMs are found to be optimal to cause selective cancer cell death, which is confirmed in both cultured cells and syngeneic tumor models, where they also reduce metastasis formation. These results show that upon tuning NM chemical composition, NMs can be designed as a targeted selective anticancer therapy.

Theoretical modeling of HPV: QSAR and novodesign with fragment approach.

Structure-activity relationships in a data set of HPV6-E1 helicase ATPase inhibitors were investigated based on two different sets of descriptors. Statistically significant four parameter Quantitative Structure-Activity Relationships (QSAR) models were constructed and validated in both cases (R(2)=0.849; R(2) cv=0.811; F=52.20; s(2)=0.25; N=42). A Fragment based QSAR (FQSAR) approach was applied for developing a fragment-QSAR equation, which enabled the construction of virtual structures for novel ATPase inhibitors with desired or pre-defined activity.

Gas-phase lithium cation basicity: revisiting the high basicity range by experiment and theory.

According to high level calculations, the upper part of the previously published FT-ICR lithium cation basicity (LiCB at 373 K) scale appeared to be biased by a systematic downward shift. The purpose of this work was to determine the source of this systematic difference. New experimental LiCB values at 373 K have been measured for 31 ligands by proton-transfer equilibrium techniques, ranging from tetrahydrofuran (137.2 kJ mol(-1)) to 1,2-dimethoxyethane (202.7 kJ mol(-1)). The relative basicities (ΔLiCB) were included in a single self-consistent ladder anchored to the absolute LiCB value of pyridine (146.7 kJ mol(-1)). This new LiCB scale exhibits a good agreement with theoretical values obtained at G2(MP2) level. By means of kinetic modeling, it was also shown that equilibrium measurements can be performed in spite of the formation of Li(+) bound dimers. The key feature for achieving accurate equilibrium measurements is the ion trapping time. The potential causes of discrepancies between the new data and previous experimental measurements were analyzed. It was concluded that the disagreement essentially finds its origin in the estimation of temperature and the calibration of Cook's kinetic method.

Computational study of the Sonogashira cross-coupling reaction in the gas phase and in dichloromethane solution.

The Sonogashira cross-couplig reaction, consisting of oxidative addition, cis-trans isomerization, transmetalation, and reductive elimination, was computationally modeled using the DFT B3LYP/cc-pVDZ method for reaction between bromobenzene and phenylacetylene. Palladium diphosphane was used as a catalyst, copper(I) bromide as a co-catalyst and trimethylamine as a base. The reaction mechanism was studied both in the gas phase and in dichloromethane solution using PCM method. The complete catalytic cycle is thermodynamically strongly shifted toward products (diphenylacetylene and regenerated palladium catalyst) and is exothermic being in accordance with experimental data. The rate-determining step is the oxidative addition, since the highest point on the Gibbs energy graph of the complete reaction is the transition state of this step. This conclusion is also supported by recent experimental data. The computed energy profile suggests that the transmetalation step is initiated by the dissociation of neutral ligand, while the activation Gibbs energy of this step is 0.1 kcal mol(-1) in the gas phase.