Molecular Structure of Phenytoin: NMR, UV-Vis and Quantum Chemical Calculations

Due to the presence of the carbonyl and imide groups in the structure of 5,5-diphenylhydantoin (DPH), the possibility for this compound to be involved in hydrogen bonding intermolecular interactions is obvious. Even though such interactions are presumably responsible for the mechanism of action of this drug, however, to the best of our knowledge, the self-hydrogen bonding interactions between the DPH monomers have not been addressed till now. Furthermore, studies reporting on the spectroscopic characteristics of this molecule are scarcely reported in the literature. Here we report on the possible dimers of DPH, investigated by quantum chemical calculations at B3LYP/6-31+G(2d,2p) level of theory. Twelve unique DPH dimers were structurally optimized in gas-phase, as well as in ethanol and DMSO and then were used to compute the population-averaged UV-Vis and NMR spectra using Boltzmann statistics. UV-Vis and NMR techniques were employed to assess experimentally the spectroscopical response of this compound. DFT calculations are also used to investigate the structural transformations between the solid and liquid phase, as well as for describing the electronic transitions and for the assignment of NMR spectra of DPH

Decreased Interactions between Calmodulin and a Mutant Huntingtin Model Might Reduce the Cytotoxic Level of Intracellular Ca2+: A Molecular Dynamics Study

Mutant huntingtin (m-HTT) proteins and calmodulin (CaM) co-localize in the cerebral cortex with significant effects on the intracellular calcium levels by altering the specific calcium-mediated signals. Furthermore, the mutant huntingtin proteins show great affinity for CaM that can lead to a further stabilization of the mutant huntingtin aggregates. In this context, the present study focuses on describing the interactions between CaM and two huntingtin mutants from a biophysical point of view, by using classical Molecular Dynamics techniques. The huntingtin models consist of a wild-type structure, one mutant with 45 glutamine residues and the second mutant with nine additional key-point mutations from glutamine residues into proline residues (9P(EM) model). Our docking scores and binding free energy calculations show higher binding affinities of all HTT models for the C-lobe end of the CaM protein. In terms of dynamic evolution, the 9P(EM) model triggered great structural changes into the CaM protein’s structure and shows the highest fluctuation rates due to its structural transitions at the helical level from α-helices to turns and random coils. Moreover, our proposed 9P(EM) model suggests much lower interaction energies when compared to the 45Qs-HTT mutant model, this finding being in good agreement with the 9P(EM)’s antagonistic effect hypothesis on highly toxic protein–protein interactions

Theoretical and Experimental Vibrational Characterization of Biologically Active Nd(III) Complex

The neodymium(III) complex of orotic acid (HOA) was synthesized and its structure determined by means of analytical and spectral analyses. Detailed vibrational analysis of HOA, sodium salt of HOA, and Nd(III)–OA systems based on both the calculated and experimental spectra confirmed the suggested metal–ligand binding mode. Significant differences in the IR and Raman spectra of the complex were observed as compared to the spectra of the ligand. The calculated vibrational wavenumbers, including IR intensities and Raman scattering activities, for the ligand and its Nd(III) complex were in good agreement with the experimental data. The vibrational analysis performed for the studied species, orotic acid, sodium salt of orotic acid, and its Nd(III) complex helped to explain the vibrational behaviour of the ligand’s vibrational modes, sensitive to interaction with Nd(III). In this paper we also report preliminary results about the cytotoxicity of the investigated compounds. The cytotoxic effects of the ligand and its Nd(III) complex were determined using the MTT method on different tumour cell lines. The screening performed revealed that the tested compounds exerted cytotoxic activity upon the evaluated cell lines

All-Atom Molecular Dynamics Investigations on the Interactions between D2 Subunit Dopamine Receptors and Three ¹¹C-Labeled Radiopharmaceutical Ligands

The D2 subunit dopamine receptor represents a key factor in modulating dopamine release. Moreover, the investigated radiopharmaceutical ligands used in positron emission tomography imaging techniques are known to bind D2 receptors, allowing for dopaminergic pathways quantification in the living human brain. Thus, the biophysical characterization of these radioligands is expected to provide additional insights into the interaction mechanisms between the vehicle molecules and their targets. Using molecular dynamics simulations and QM calculations, the present study aimed to investigate the potential positions in which the D2 dopamine receptor would most likely interact with the three distinctive synthetic 11C-labeled compounds (raclopride (3,5-dichloro-N-[[(2S)-1-ethylpyrrolidin-2-yl]methyl]-2-hydroxy-6-methoxybenzamide)—RACL, FLB457 (5-bromo-N-[[(2S)-1-ethylpyrrolidin-2-yl]methyl]-2,3-dimethoxybenzamide)—FLB457 and SCH23390 (R(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine)—SCH)), as well as to estimate the binding affinities of the ligand-receptor complexes. A docking study was performed prior to multiple 50 ns molecular dynamics productions for the ligands situated at the top and bottom interacting pockets of the receptor. The most prominent motions for the RACL ligand were described by the high fluctuations of the peripheral aliphatic -CH3 groups and by its C-Cl aromatic ring groups. In good agreement with the experimental data, the D2 dopamine receptor-RACL complex showed the highest interacting patterns for ligands docked at the receptor’s top position