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Aims: Cyclin-dependent kinase 9 (CDK9) plays a major role in the regulation of transcription. Its overexpression -which occurs in several types of cancer- increases the levels of certain antiapoptotic proteins that can lead to tumorigenesis, therefore the identification of new, more potent and more selective inhibitors is essential. Methods: In this study we present a computational approach, which can facilitate lead selection and optimization. Results: First, a pharmacophore hypothesis based on the active compounds has been developed to identify the key features for the ligand-target interaction. This was followed by the docking of the compounds into the active site of CDK9, the poses and interactions with the amino acids were compared with those of the co-crystallized ligand. The mode of their binding further explained the characteristics of these inhibitors while the docking scores can be a factor in the selection of active compounds in the future. Finally, a field-based QSAR model was also created, to predict the activity of inhibitor candidates. Conclusion: With our current work we deepened our knowledge about the interactions between CDK9 and its inhibitors, which can contribute to the discovery of novel CDK9 inhibitors.

The complement system is associated with various diseases such as inflammation or auto-immune diseases. Complement-targeted drugs could provide novel therapeutic intervention against the above diseases. C1s, a serine protease, plays an important role in the CS and could be an attractive target since it blocks the system at an early stage of the complement cascade. Designing C1 inhibitors is particularly challenging since known inhibitors are restricted to a narrow bioactive chemical space in addition selectivity over other serine proteases is an important requirement. The typical architecture of a small molecule inhibitor of C1s contains an amidine (or guanidine) residue, however, the discovery of non-amidine inhibitors might have high value, particularly if novel chemotypes and/or compounds displaying improved selectivity are identified. We applied various virtual screening approaches to identify C1s focused libraries that lack the amidine/guanidine functionalities, then the in silico generated libraries were evaluated by in vitro biological assays. While 3D structure-based methods were not suitable for virtual screening of C1s inhibitors, and a 2D similarity search did not lead to novel chemotypes, pharmacophore model generation allowed us to identify two novel chemotypes with submicromolar activities. In three screening rounds we tested altogether 89 compounds and identified 20 hit compounds (&lt, 10 &mu, M activities, overall hit rate: 22.5%). The highest activity determined was 12 nM (1,2,4-triazole), while for the newly identified chemotypes (1,3-benzoxazin-4-one and thieno[2,3-d][1,3]oxazin-4-one) it was 241 nM and 549 nM, respectively.

The phospholipid derivative lysophosphatidic acid (LPA) serves as a signalling molecule through the activation of LPA receptors, which belong to the G-protein-coupled receptors. From a pharmacological point of view, the (‘EDG-like’) LPA 1-3 receptors have attracted much attention, therefore we have also been focusing in our study on these subtypes. The LPA1receptors are widely expressed in the human body; interestingly, LPA 1 might have a role in the pathomechanism of obesity. In order to recognize key structural features of the molecular interactions of human LPA 1 with its agonists, we built up the 3D structure of the LPA 1 through homology modeling. Next, LPA 1 agonists and antagonists were docked into the model. The mode of binding and the interactions between ligands and key amino acids (R3.28 and Q3.29) were consistent with mutagenesis assays and previously published models, indicating that this model is able to discriminate high-affinity compounds and may be useful for the development of novel agonists of LPA 1 . Homology models were also constructed for LPA 2 and LPA 3 . All available agonists with published EC 50 values, antagonists with IC 50 values and compounds with K i values for either of LPA 1 , LPA 2 or LPA 3 were collected from the ChEMBL database and were docked into the corresponding model.Ourmodels for the LPA 1-3 receptors can discriminate high-affinity compounds identified in silico HTS studies and may be useful for the development of novel agonistsof LPA receptors. With a better understanding of the differences between LPA 1-3 receptors new, selective agonists and antagonist could be designed, which could be used in the therapy of various diseases with a better side-effect profile.

To develop novel neuroprotective agents, a library of novel arylalkenylpropargylamines was synthesized and tested for inhibitory activities against monoamine oxidases. From this, a number of highly potent and selective monoamine oxidase B inhibitors were identified. Selected compounds were also tested for neuroprotection in in vitro studies with PC-12 cells treated with 6-OHDA and rotenone, respectively. It was observed that some of the compounds tested yielded a marked increase in survival in PC-12 cells treated with the neurotoxins. This indicates that these propargylamines are able to confer protection against the effects of the toxins and may also be considered as novel disease-modifying anti-Parkinsonian agents, which are much needed for the therapy of Parkinson's disease.

Background: Isoindolo[2,1-alpha] quinoxalines constitute an important class of compounds which demonstrated potent antiproliferative activity against different human tumor cell lines and topoisomerase I inhibitors. In particular, their water soluble imine or iminium salts recently synthesized showed potent growth inhibitory effect on NCI-60 tumor cell line panel and biological studies performed on the most active compounds demonstrated that they cause DNA damage via topoisomerase I poisoning. Objective: Herein, we investigate with molecular modeling methods, the common features responsible for topoisomerase I inhibition of the water-soluble isoindolo[2,1-alpha] quinoxalin-6-imines, by comparing them with known inhibitors. Methods: Different X-ray crystallographic structures with co-crystallized inhibitors were investigated and their binding modes were analyzed. The structures of the inhibitors were also compared through a pharmacophore analysis. As a validation of our docking method, the co-crystallized inhibitors were re-docked. Conclusion: Our docking studies performed on Isoindolo[2,1-alpha] quinoxalines and other inhibitors revealed very important common features responsible for topoisomerase I inhibition that can improve the design of new inhibitors.

International audience; Piceatannol is a hydroxylated derivative of resveratrol. While both dietary polyphenols coexist in edible plants and fruits, and share equivalent concentrations in several wines, the influence of piceatannol on adiposity has been less studied than that of resveratrol. Though resveratrol is now recognized to limit fat deposition in various obesity models, the benefit of its dietary supplementation remains under debate regarding human obesity treatment or prevention. The research for more potent resveratrol analogs is therefore still undergoing. This prompted us to compare various effects of piceatannol and resveratrol directly on human adipose tissue (hAT). Hydrogen peroxide release was measured by Amplex Red-based fluorescence in subcutaneous hAT samples from obese patients. Interactions of stilbenes with human amine oxidases and quinone reductase were assessed by radiometric methods, computational docking and electron paramagnetic resonance. Influences on lipogenic and lipolytic activities were compared in mouse adipocytes. Resveratrol and piceatannol inhibited monoamine oxidase (MAO) with respective IC50 of 18.5 and 133.7 μM, but not semicarbazide-sensitive amine oxidase (SSAO) in hAT. For both stilbenes, the docking scores were better for MAO than for SSAO. Piceatannol and resveratrol similarly hampered hydrogen peroxide detection in assays with and without hAT, while they shared pro-oxidant activities when incubated with purified quinone reductase. They exhibited similar dose-dependent inhibition of adipocyte lipogenic activity. Only piceatannol inhibited basal and stimulated lipolysis when incubated at a dose ≥100 μM. Thus, piceatannol exerted on fat cells dose-dependent effects similar to those of resveratrol, except for a stronger antilipolytic action. In this regard, piceatannol should be useful in limiting the lipotoxicity related to obesity when ingested or administered alone - or might hamper the fat mobilization induced by resveratrol when simultaneously administered with it.

Kalotaszeg is a famous historic and ethnographic region in Transylvania (Romania) consisting of approximately 35–40 village communities. The region has raised considerable scholarly interest since its early discovery at the end of the 19th century. A constantly reoccurring focus of studies has been to outline the structure of the region. Although it was not our primary concern, when we started our social anthropology fi eldwork at the beginning of the 1990s we soon encountered the problematic issue of how to delineate the external and internal boundaries around and within this multi-ethnic and multi-religious region and how to grasp in-group and out-group relations with a special regard to the context of socio-historical structure of the population in the area. We wanted to understand what kinds of diachronic and synchronic factors stood behind the formation of various networks of human connection interpreted as regional structures.

Vascular adhesion protein-1 (VAP-1)/semicarbazide-sensitive amine oxidase (SSAO) is an adhesion protein involved in leukocyte trafficking and inflammatory processes, with a special amine oxidase activity. Inhibitors have been mainly developed for treating chronic inflammatory disorders. The utility of inhibitors as antiangiogenic agents in ophthalmological and oncological diseases is currently under evaluation. SSAO substrates may mimic several insulin effects, although their utility for the treatment of diabetes is still far from being fully understood.This paper reviews the patent literature of SSAO/VAP-1 inhibitors and substrates, for the period of 1990 - 2010. The current stage of SSAO/VAP-1-interacting agents published in patents is described, along with their chemical structures and pharmacological uses.SSAO/VAP-1 is a promising anti-inflammatory target. Another important field for therapeutic application of these inhibitors may be ophthalmology, due to their antiangiogenic effects. SSAO substrates might also be of therapeutic value in the treatment of diabetes; however, more extensive research has to be undertaken to validate this approach.

Background: Benzylamine exerts insulin-like effects in adipocytes (e.g., glucose uptake and antilipolysis) and improves glucose handling in rodents. Results: In murine adipocytes, benzylamine mimics another insulin action: it enhances apelin expression in a manner that is blocked by the semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) inhibitor semicarbazide. It is shown that in human adipocytes, benzylamine activates glucose transport, but its effects are not additive to maximal insulin stimulation. Benzylamine effects are hydrogen peroxide dependent. They can be reproduced by novel substrates, but not by benzaldehyde. Conclusion: Owing to the parallelism between the in vitro insulin mimicry and the in vivo improvement of glucose handling elicited by benzylamine in rodents, the SSAO/VAP-1 substrates, with stronger effects on human adipocytes than benzylamine, show promising applications for the treatment of insulin resistance.

The therapeutic usefulness of current agents that activate the three α 2 -adrenoceptors, α 2A , α 2B and α 2C is limited by their lack of subtype selectivity. One approach to the development of subtype-selective agents is the in silico docking of potential ligands to the receptors in quantitative molecular modeling studies. Because the crystal structure of the α 2 -adrenoceptors is not known, we used homology modeling based on the published structure of bovine rhodopsin. We developed individual models for each of the three receptors, which were found to accurately represent published data from both radioligand binding mutagenesis experiments. Using 18 non-subtype-selective agents to validate the models, the calculated transformed and the experimental binding free energies were satisfactory correlated ( r 2 A = 0.888, r 2 B = 0.887, r 2 C = 0.790). The binding pockets differed in size (482–619 A 3 ) with the α 2B receptor subtype having the largest and the α 2c the smallest cavity. The binding sites for all three subtypes were found to be essentially identical with the exception of two subtype-specific residues, and thus we were unable to identify any significant differences in the interactions of ligands with the three receptor subtypes. Although, the binding properties of all three receptors are very similar, the differences in pocket volume and two subtype-specific residues in the binding pocket might play an as yet undocumented role in subtype selectivity.

Isoflavones are suitable guest molecules for inclusion complex formation with cyclodextrins (CDs). The molecular encapsulation with CDs results in a solid, molecularly dispersed form and in a significantly improved aqueous solubility of isoflavones. Genistein, a key isoflavone constituent of Ononidis spinosae radix was found to form a supramolecular, non-covalent inclusion complex with both beta-cyclodextrin (beta-CD) and gamma-cyclodextrin (gamma-CD), while it did not form a stable complex with alpha-CD. The guest genistein was found to spatially located in the less polar cavity of cyclodextrin. The isolated binary genistein/CD complexes appeared novel crystalline lattices. The in vitro dissolution of genistein entrapped into both beta- and gamma-CD, significantly surpassed that of the plain isoflavone.

The paper aims to look at those community-organizing phenomena that provided alternatives to officially supported, mandatory youth activities and played a vital role in the everyday life of young people in socialist Hungary in the 1970s and 80s. The urban folk dance and music revival, the so-called tanchaz (dance house) movement, is highlighted. The authors argue that the dance house as a subculture with its concept of “authenticity” was able to create common identity with the intrinsic notion of oppositional stance. Parallels are drawn between sports, rock music, literature and the dance house. The process of disintegration and folkloristic discovery of traditional peasant culture in Hungary and in Transylvania, communist peasant policy, and the connections between cities and villages are discussed alongside the phenomena of revival and issues of identity.

The oxytocin receptor belongs to class A receptors within the great family of G protein-coupled receptors. The endogenous ligand oxytocin is a nonapeptide hormone that induces the uterine contractions at parturition and is used to induce the labor. The peptide oxytocin and, even more, its non-peptide antagonist, could be valuable tools in tocolysis. The knowledge of the three-dimensional structure of the oxytocin receptor and the determination of the main interaction points between the receptor and the ligands may help to develop selective oxytocin agonists and antagonist. This review summarizes the knowledge about the mapping of the binding domain of the oxytocin receptor and the efforts in the field of molecular modeling studies related to oxytocin receptor-ligand interactions.

Three-dimensional structure-activity relationship studies of alpha2a-adrenoceptor agonists were carried out by Distance Comparison (DISCOthech) and Comparative Molecular Field Analysis (CoMFA) methods to define the pharmacophore and a quantitative model, respectively, of this class of compounds. The statistical validation of the CoMFA model indicates its high predictive performance for binding affinities of new alpha2a-adrenoceptor agonists.

Resveratrol has been reported to inhibit monoamine oxidases (MAO). Many substrates or inhibitors of neuronal MAO interact also with other amine oxidases (AO) in peripheral organs, such as semicarbazide-sensitive AO (SSAO), known as primary amine oxidase, absent in neurones, but abundant in adipocytes. We asked whether phenolic compounds (resveratrol, pterostilbene, quercetin, and caffeic acid) behave as MAO and SSAO inhibitors. AO activity was determined in human adipose tissue. Computational docking and glucose uptake assays were performed in 3D models of human AO proteins and in adipocytes, respectively. Phenolic compounds fully inhibited the fluorescent detection of H2O2generated during MAO and SSAO activation by tyramine and benzylamine. They also quenched H2O2-induced fluorescence in absence of biological material and were unable to abolish the oxidation of radiolabelled tyramine and benzylamine. Thus, phenolic compounds hampered H2O2detection but did not block AO activity. Only resveratrol and quercetin partially impaired MAO-dependent [14C]-tyramine oxidation and behaved as MAO inhibitors. Phenolic compounds counteracted the H2O2-dependent benzylamine-stimulated glucose transport. This indicates that various phenolic compounds block downstream effects of H2O2produced by biogenic or exogenous amine oxidation without directly inhibiting AO. Phenolic compounds remain of interest regarding their capacity to limit oxidative stress rather than inhibiting AO.

Water-soluble isoindoloquinoxalin (IIQ) imines and the corresponding acetates were conveniently prepared from the key intermediates 2-(2′-aminophenyl)-2H-isoindole-1-carbonitriles obtained by a Strecker reaction between substituted 1,2-dicarbaldehydes and 1,2-phenylenediamines. Both series were screened by the National Cancer Institute (Bethesda, MD) and showed potent antiproliferative activity against a panel of 60 human tumor cell lines. Several of the novel compounds showed GI50 values at a nanomolar level on the majority of the tested cell lines. Among IIQ derivatives, methoxy substituents at positions 3 and 8 or/and 9 were especially effective in impairing cell cycle progression and inducing apoptosis in cancer cells. These effects were associated to IIQ-mediated impairment of tubulin polymerization at pharmacologically significant concentrations of tested compounds. In addition, impaired DNA topoisomerase I functions and perturbation in telomere architecture were observed in cells exposed to micromolar concentrations of IIQ derivatives. The above results suggest that IIQ derivatives exhibit multi-target cytotoxic activities.

A reliable quantitative model for estimation of reactivities of Diels–Alder reactions has been developed. A linear and a non-linear method were used to predict rate constants. Computationally efficient descriptors (including chemical graph indices, intermolecular binding distances, molecular surface areas and electrostatic potentials (ESP), ESP atom value autocorrelation functions, topological (2D) or topographical parameters) with artificial neural networks as well as calculated IR-spectra (Sybyl's EVA) with partial least square regression were used to build the QSPR equations. Both sets of descriptors are invariant to roto-translation.

Ten pairs of pyridazinone regioisomers were prepared, and their lipophilicity was described by the logarithm of the octanol/water partition coefficient (log P) determined experimentally and calculated with prediction methods. The 4- and 5-(substituted amino)-3(2H)-pyridazinone regioisomers were synthesized by nucleophilic substitution of one of the chloro atoms of 4,5-dichloro-2-methyl-3(2H)-pyridazinone or its 6-nitro derivative. Structures of new compounds were proven by spectroscopic methods. The experimental log P values were obtained by a shake flask method in octanol and a Sörensen buffer (pH 7.4) solvent system. A consequent difference was found in the lipophilicity of regioisomers. For each isomer pair, the log P value of the 4-isomer was significantly (average by 0.75 log unit) higher than that of the 5-isomer. Some quantum chemical calculations as well as X-ray analysis of two pairs of regioisomers were also carried out to gain insight into the structural differences of regioisomers. The log P values were calculated by the fragmental approach KOWWIN and a QSPR analysis (3DNET). The a priori KOWWIN gave poor agreement, but with the programs KOWWIN with EVA (experimental value adjusted) and 3DNET, the results were generally in agreement with experiment.

The hydroformylation of styrene was carried out in the presence of in situ rhodium catalysts containing 1-arylphospholes with different substituents in position 2 or 3. The aryl substituents were varied from phenyl to different sterically hindered 2,4,6-trialkylphenyls. The structures and Bird-indices (BIs) of the phospholes with different steric and electronic properties were determined by DFT calculations. High chemoselectivities towards hydroformylation, as well as regioselectivities towards the branched formyl regioisomer (2-phenyl-propanal) were obtained at a temperature of 40 °C. Similarly, high chemoselectivity was accompanied by a decreased regioselectivity at 100 °C. The phospholes with an exocyclic P-function in position 2 or 3 showed higher catalytic activity.

N-methylation is a naturally occurring modification in small peptides, e.g. antibiotics that can effect the conformational preferences of the molecule as well as the ease of trans to cis isomerization of the involved peptide bond. In the present exploratory study we have calculated the potential energy surface of both N -acetyl- l -alanine- N ′-methylamide and N -acetyl- N -methyl- l -alanine- N ′-methylamide at the RHF/3-21G level of theory with a cis – trans or with a trans – trans peptide conformation. With respect to the non-methylated model system our results indicate that N-methylation reduces the number of observable backbone conformers in both amide configurations. The effect of methylation on the ease of trans to cis isomerization was assessed by calculating the energetics of the corresponding transition structures. An increase in the activation energies of the trans to cis isomerization of the relevant peptide bond was observed for the N-methylated moiety.

Condensed O,N-heterocycles containing tetrahydro-1,4-benzoxazepine and tetrahydroquinoline moieties were prepared by a regio- and diastereoselective domino Knoevenagel–[1,5]-hydride shift cyclization reaction of a 4-aryl-2-phenyl-1,4-benzoxazepine derivative obtained from flavanone. The relative configuration of products were determined by the correlation of 3JH,H coupling data with the geometry of major conformers accessed by DFT conformational analysis. Separated enantiomers of the products were characterized by HPLC-ECD data, which allowed their configurational assignment on the basis of TDDFT-ECD calculation of the solution conformers. Two compounds showed neuroprotective activities against hydrogen peroxide (H2O2) or β-amyloid25–35 (Aβ25–35)-induced cellular injuries in human neuroblastoma SH-SY5Y cells in the range of those of positive controls.

Movement disorders are a heterogeneous group of both common and rare neurological conditions characterized by abnormalities of motor functions and movement patterns. This work overviews recent successes and ongoing studies of repositioning relating to this disease group, which underscores the challenge of integrating the voluminous and heterogeneous findings required for making suitable drug repositioning decisions. In silico drug repositioning methods hold the promise of automated fusion of heterogeneous information sources, but the controllable, flexible and transparent incorporation of the expertise of medicinal chemists throughout the repositioning process remains an open challenge. In support of a more systematic approach toward repositioning, we summarize the application of a computational repurposing method based on statistically rooted knowledge fusion. To foster the spread of this technique, we provide a step-by-step guide to the complete workflow, together with a case study in Parkinson's disease.

The therapeutic usefulness of current agents that activate the three alpha(2)-adrenoceptors, alpha(2A), alpha(2B) and alpha(2C) is limited by their lack of subtype selectivity. One approach to the development of subtype-selective agents is the in silico docking of potential ligands to the receptors in quantitative molecular modeling studies. Because the crystal structure of the alpha(2)-adrenoceptors is not known, we used homology modeling based on the published structure of bovine rhodopsin. We developed individual models for each of the three receptors, which were found to accurately represent published data from both radioligand binding mutagenesis experiments. Using 18 non-subtype-selective agents to validate the models, the calculated transformed and the experimental binding free energies were satisfactory correlated (r(2)(A)=0.888, r(2)(B)=0.887, r(2)(C)=0.790). The binding pockets differed in size (482-619A(3)) with the alpha(2B) receptor subtype having the largest and the alpha(2c) the smallest cavity. The binding sites for all three subtypes were found to be essentially identical with the exception of two subtype-specific residues, and thus we were unable to identify any significant differences in the interactions of ligands with the three receptor subtypes. Although, the binding properties of all three receptors are very similar, the differences in pocket volume and two subtype-specific residues in the binding pocket might play an as yet undocumented role in subtype selectivity.

Isoflavones are suitable guest molecules for inclusion complex formation with cyclodextrins (CDs). The molecular encapsulation with CDs results in a solid, molecularly dispersed form and in a significantly improved aqueous solubility of isoflavones. Genistein, a key isoflavone constituent of Ononidis spinosae radix was found to form a supramolecular, non-covalent inclusion complex with both beta-cyclodextrin (beta-CD) and gamma-cyclodextrin (gamma-CD), while it did not form a stable complex with alpha-CD. The guest genistein was found to spatially located in the less polar cavity of cyclodextrin. The isolated binary genistein/CD complexes appeared novel crystalline lattices. The in vitro dissolution of genistein entrapped into both beta- and gamma-CD, significantly surpassed that of the plain isoflavone.