Malaria is nowadays a worldwide and serious problem with a significant social, economic, and human cost, mainly in developing countries. In addition, the emergence and spread of resistance to ...existing antimalarial therapies deteriorate the global malaria situation, and lead thus to an urgent need toward the design and discovery of new antimalarial drugs. In this work, a QSAR predictive model based on GETAWAY descriptors was developed which is able to explain with, only three variables, more than 77% of the variance in antimalarial potency and displays a good internal predictive ability (of 73.3% and 72.9% from leave-one-out cross-validation and bootstrapping analyses, respectively). The performance of the proposed model was judged against other five methodologies providing evidence of the superiority of GETAWAY descriptors in predicting the antimalarial potency of the bisbenzamidine family. Moreover, a desirability analysis based on the final QSAR model showed that to be a useful way of selecting the predictive variable level necessary to obtain potent bisbenzamidines. From the proposed model it is also possible to infer that elevated high atomic masses/polarizabilities/van der Waals volumes could play a negative/positive/positive role in the molecular interactions responsible for the desired drug conformation, which is required for the optimal binding to the macromolecular target. The results obtained point out that our final QSAR model is statistically significant and robust as well as possessing a high predictive effectiveness. Thus, the model provides a feasible and practical tool for looking for new and potent antimalarial bisbenzamidines.
Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging ...studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 × 10
), left fusiform gyrus (d=-0.288; P=8.25 × 10
) and left rostral middle frontal cortex (d=-0.276; P=2.99 × 10
). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.
A comparison between (a) experimental and (b) theoretical (B3LYP/6-31G(d,p)-PCM (DMSO)) 1H NMR spectra can be used for determination of the conformation of the B ring of flavonoids polyphenols, ...important natural antioxidants, in solution (inter-ring torsion angle, φ1, and some hydrogen atoms distances for Epigallocatechin is shown).
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•Experimental and theoretical 1H NMR chemical shift patterns, calculated using DFT.•Theoretical prediction molecular structure of flavonoids in solution.•The best match between B3LYP/6-31G(d,p)-PCM and experimental 1H NMR spectra.•Rotated B-ring polyphenol structures leads to the best agreement with NMR experiment.•Determination of conformation of flavonoids in solution through NMR spectra analysis.
In this work, we showed that comparison between experimental and theoretical 1H NMR chemical shift patterns, calculated using Density Functional Theory (DFT), can be used for the prediction of molecular structure of flavonoids in solution, what is experimentally accessible for gas phase (electron diffraction methods) and solid samples (X-ray diffraction). The best match between B3LYP/6-31G(d,p)-PCM 1H NMR calculations for B ring rotated structures and experimental spectra can provide information on the conformation adopted by polyphenols in solution (usually DMSO-d6, acetone-d6 as solvents), which may differ from solid state and gas phase observed structures, and also DFT optimized geometry in the vacuum.
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