Molecular modeling, mutational analysis and steroid specificity of the ligand binding pocket of mPRα (PAQR7): Shared ligand binding with AdipoR1 and its structural basis.

The 7-transmembrane architecture of adiponectin receptors (AdipoRs), determined from their X-ray crystal structures, was used for homology modeling of another progesterone and adipoQ receptor (PAQR) family member, membrane progesterone receptor alpha (mPRα). The mPRα model identified excess positively charged residues on the cytosolic side, suggesting it has the same membrane orientation as AdipoRs with an intracellular N-terminus. The homology model showed identical amino acid residues to those forming the zinc binding pocket in AdipoRs, which strongly implies that zinc is also present in mPRα.

KNIME-based Analysis of Off-Target Effect of Drugs Related to The Molecular 2D Fingerprint.

Purpose: Structurally similar molecules are likely to have similar biological activity. In this study, similarity searching based on molecular 2D fingerprint was performed to analyze off-target effects of drugs. The purpose of this study is to determine the correlation between the adverse effects and drug off-targets.

QSAR-based molecular signatures of prenylated (iso)flavonoids underlying antimicrobial potency against and membrane-disruption in Gram positive and Gram negative bacteria.

Prenylated flavonoids and isoflavonoids are phytochemicals with remarkable antibacterial activity. In this study, 30 prenylated (iso)flavonoids were tested against Listeria monocytogenes and Escherichia coli (the latter in combination with an efflux pump inhibitor). Minimum inhibitory concentrations of the most active compounds ranged between 6.

Molden 2.0: quantum chemistry meets proteins.

Since the first distribution of Molden in 1995 and the publication of the first article about this software in 2000 work on Molden has continued relentlessly. A few of the many improved or fully novel features such as improved and broadened support for quantum chemistry calculations, preparation of ligands for use in drug design related softwares, and working with proteins for the purpose of ligand docking.

Structural basis for non-genuine phenolic acceptor substrate specificity of Streptomyces roseochromogenes prenyltransferase CloQ from the ABBA/PT-barrel superfamily.

Acceptor substrate specificity of Streptomyces roseochromogenes prenyltransferase SrCloQ was investigated using different non-genuine phenolic compounds. RP-UHPLC-UV-MSn was used for the tentative annotation and quantification of the prenylated products. Flavonoids, isoflavonoids and stilbenoids with different types of substitution were prenylated by SrCloQ, although with less efficiency than the genuine substrate 4-hydroxyphenylpyruvate.

Visually impaired researchers get their hands on quantum chemistry: application to a computational study on the isomerization of a sterol.

In molecular sciences, articles tend to revolve around 2D representations of 3D molecules, and sighted scientists often resort to 3D virtual reality software to study these molecules in detail. Blind and visually impaired (BVI) molecular scientists have access to a series of audio devices that can help them read the text in articles and work with computers. Reading articles published in this journal, though, is nearly impossible for them because they need to generate mental 3D images of molecules, but the article-reading software cannot do that for them.

Enzyme-specific activation versus leaving group ability.

Enzyme-specific activation and the substrate mimetics strategy are effective ways to circumvent the limited substrate recognition often encountered in protease-catalyzed peptide synthesis. A key structural element in both approaches is the guanidinophenyl (OGp) ester, which enables important interactions for affinity and recognition by the enzyme--at least, this is usually the explanation given for its successful application. In this study we show that leaving group ability is of equal or even greater importance.

Phenylalanine 368 of multidrug resistance-associated protein 4 (MRP4/ABCC4) plays a crucial role in substrate-specific transport activity.

Multidrug resistance-associated protein 4 (MRP4) is a membrane transporter that mediates the cellular efflux of a wide range of anionic drugs and endogenous molecules. MRP4 transport can influence the pharmacokinetics of drugs and their metabolites, therefore more knowledge about the molecular determinants important for its transport function would be of relevance. Here, we substituted amino acids Phe(368), Trp(995), and Arg(998) with conservative or non-conservative residues, and determined the effect on transport of the model substrates estradiol 17-β-d-glucuronide (E(2)17βG), cyclic guanosine monophosphate (cGMP), methotrexate (MTX), and folic acid into membrane vesicles isolated from baculovirus transduced HEK293 cells overexpressing the mutant MRP4 proteins.

Triazole fungicides can induce cross-resistance to medical triazoles in Aspergillus fumigatus.

Background: Azoles play an important role in the management of Aspergillus diseases. Azole resistance is an emerging global problem in Aspergillus fumigatus, and may develop through patient therapy. In addition, an environmental route of resistance development has been suggested through exposure to 14α-demethylase inhibitors (DMIs).

Quantum mechanical polar surface area.

A correlation has been established between the absorbed fraction of training-set molecules after oral administration in humans and the Quantum Mechanical Polar Surface Area (QMPSA). This correlation holds for the QMPSA calculated with structures where carboxyl groups are deprotonated. The correlation of the absorbed fraction and the QMPSA calculated on the neutral gas phase optimized structures is much less pronounced.

The structure-function relationship of the Aspergillus fumigatuscyp51A L98H conversion by site-directed mutagenesis: the mechanism of L98H azole resistance.

Since 1998, the rapid emergence of multi-azole-resistance (MAR) was observed in Aspergillus fumigatus in the Netherlands. Two dominant mutations were found in the cyp51A gene, a 34bp tandem repeat (TR) in the promoter region combined with a leucine to histidine substitution at codon 98 (L98H). In this study, we show that molecular dynamics simulations combined with site-directed mutagenesis of amino acid substitutions in the cyp51A gene, correlate to the structure-function relationship of the L98H substitution conferring to MAR in A.

Azole resistance profile of amino acid changes in Aspergillus fumigatus CYP51A based on protein homology modeling.

Molecular studies have shown that the majority of azole resistance in Aspergillus fumigatus is associated with amino acid substitutions in the cyp51A gene. To obtain insight into azole resistance mutations, the cyp51A gene of 130 resistant and 76 susceptible A. fumigatus isolates was sequenced.

The non-gastric H,K-ATPase as a tool to study the ouabain-binding site in Na,K-ATPase.

Based on studies with chimeras between (non-)gastric H,K-ATPase and Na,K-ATPase, a model for the ouabain binding site has recently been presented (Qiu et al. J.Biol.

QCRNA 1.0: a database of quantum calculations for RNA catalysis.

This work outlines a new on-line database of quantum calculations for RNA catalysis (QCRNA) available via the worldwide web at http://theory.chem.umn.

Reconstruction of the complete ouabain-binding pocket of Na,K-ATPase in gastric H,K-ATPase by substitution of only seven amino acids.

Although cardiac glycosides have been used as drugs for more than 2 centuries and their primary target, the sodium pump (Na,K-ATPase), has already been known for 4 decades, their exact binding site is still elusive. In our efforts to define the molecular basis of digitalis glycosides binding we started from the fact that a closely related enzyme, the gastric H,K-ATPase, does not bind glycosides like ouabain. Previously, we showed that a chimera of these two enzymes, in which only the M3-M4 and M5-M6 hairpins were of Na,K-ATPase, bound ouabain with high affinity (Koenderink, J.