We examined the correlation between the Car-Parrinello sampled anharmonic frequency of the OH stretching motion and the corresponding instantaneous geometric parameters associated with the structure of crystalline sodium hydrogen bis(sulfate). The absence of appreciable correlations gives strong evidence of the extreme complexity of short hydrogen bonding.
COBISS.SI-ID: 4992794
In order to investigate features essential for the modes of action of MAO, we have calculated pKa values of three relevant tyrosine residues in the MAO B active site, with and without dopamine bound as the substrate (as well as the pKa of the dopamine itself in the active site). In conjunction with additional experimental and computational work, the data presented here should lead toward a deeper understanding of mechanisms of the catalytic activity and irreversible inhibition of MAO B, which can allow for the design of novel and improved MAO B inhibitors.
COBISS.SI-ID: 4948506
Monoamine oxidases (MAOs) are flavoenzymes important in regulating amine neurotransmitter levels and are the central pharmacological targets in treating depression and Parkinson's disease. On the basis of quantum chemical calculations, we have proposed a new two-step hydride mechanism for the MAO-catalysed oxidative deamination of amines. In the rate-limiting first step, through its N5 atom, the flavin abstracts a hydride anion from the substrate \alpha-carbon atom and forms a strong covalent adduct with the thus created cation. This is followed by flavin N1 deprotonation of the substrate amino group, facilitated with two active-site water molecules, to produce fully reduced flavin, FADH2, and neutral imine. We have demonstrated that our mechanism is in agreement with available experimental data and provided evidence against both traditional polar nucleophilic and single-electron radical pathways. These results provide valuable information for mechanistic studies on other flavoenzymes and for the design of new antidepressants and antiparkinsonian drugs.
COBISS.SI-ID: 5142810
Bacterial DNA gyrase is a well-established and validated target for the development of novel antibacterials. Starting from the available structural information about the binding of the natural product inhibitor, clorobiocin, we identified a novel series of 4ʼ-methyl-N2-phenyl-[4,5ʼ-bithiazole]-2,2ʼ-diamine inhibitors of gyrase B witha low micromolar inhibitory activity, by implementing a two-step structure-based design procedure. This novel class of DNA gyrase inhibitors was extensively investigated by various techniques (differential scanning fluorimetry, surface plasmon resonance and microscale thermophoresis). The binding mode of the potent inhibitor 18 was revealed by X-ray crystallography,confirming our initial in silico binding model. Furthermore, the high resolution of the complex structure allowed for the placement of the Gly97-Ser108 flexible loop, thus revealing its role in binding of this class of compounds. The crystal structure of the complex protein G24 and inhibitor 18 provides valuable information for further optimization of this novel class of DNA gyrase B inhibitors.
COBISS.SI-ID: 4999450
Using a combination of genomic and post-genomic approaches is rapidly alteringthe number of identified human influx carriers. A transmembrane protein bilitranslocase (TCDB 2.A.65) has long attracted attention because of its function as an organic anion carrier. It has also been identified as a potential membrane transporter for cellular uptake of several drugs and due toits implication in drug uptake, it is extremely important to advance the knowledge about its structure. However, at present, only the primary structureof bilitranslocase is known. In our work, transmembrane subunits of bilitranslocase were predicted by a previously developed chemometrics model and the stability of these polypeptide chains were studied by molecular dynamics (MD) simulation. Furthermore, sodium dodecyl sulfate (SDS) micelles were used as a model of cell membrane and herein we present a high-resolution 3D structure of an 18 amino acid residues long peptide corresponding to the third transmembrane part of bilitranslocase obtained by use of multidimensional NMR spectroscopy. It has been experimentally confirmed that one of the transmembrane segments of bilitranslocase has alpha helical structure with hydrophilic amino acid residues oriented towards one side, thuscapable of forming a channel in the membrane
COBISS.SI-ID: 4993562