Development Of New Substances Research Articles

IN SILICO STUDIES OF TUMOUR TARGETED PEPTIDE DERIVED FROM PROTEASE PRODUCED BY BACILLUS CEREUS HN FOR TARGETING WNT SIGNALLING PATHWAY USING MOLECULAR DOCKING AND MOLECULAR DYNAMICS

Background:In todays world, its becoming increasingly difficult to ignore the role of cancer in social health. Breast cancer remains the second global cause of death in women. Alterations disrupt normal cell function, cause cancerous cells to over-proliferate, and avoid mechanisms that might typically control their growth, division, and migration. A disruption in signalling pathways, a mutation that might lead to overexpression of certain genes that can, in turn, activate the signalling pathway and send it into an override mode that leads to diseases such as cancers. These signalling pathways can be targeted not only for use as biomarkers for the early detection of certain cancers but also for targeted treatment of cancers. The prospect of the development of new substances with antitumoral potential is of great importance for thetreatment of breast cancer. Result:The objective of this work is to design a peptide from a laboratory-produced Protease enzyme isolated from Bacillus cereus HNand use that as a drug or ligand that could potentially bind to the LRP5 protein and inactivate the Wntsignalling pathway in triple-negative breast cancer cells. Conclusion:The work was aimed at computational modelling of a safe peptide which followed the pharmacokinetic parameters and conducting docking analysis to assess the binding free energy between LRP 5 and the designed peptide. The docking results show that the ligand is a good candidate for novel drug development. The models created and analysed in this work will most certainly help in future research on targeting the Wntsignalling pathway and its components.

Algorithm for the development of a multicomponent pharmaceutical substance of plant origin with antimicrobial action: from science search to dosage form

Introduction. Despite the proven clinical efficacy of antifungal and anti-inflammatory drugs for the prevention and treatment of seborrheic dermatitis, the search for new targets and the development of new substances with a beneficial effect on the scalp microflora, with a low risk of antimicrobial resistance and adverse effects, are relevant.Aim. Development of the antimicrobial multicomponent pharmaceutical substance of plant origin in stages: from a literature search for promising substances, analysis of their composition by GC-MS, in silico evaluation of the affinity of individual components to pathogenetic targets, selection of the optimal composition of a multicomponent substance based on the results of in vitro research of antimicrobial action and the making of a medical dosage form based on it – a medicinal shampoo for the treatment of seborrheic dermatitis.Materials and methods. Objects of research: tea tree essential oil, 1,8-cineole, α-(-)-bisabolol and the multicomponent substance based on them. Methods: molecular docking (AutoDock version 4.2), prediction of pharmacological activity (Phyto4Health), TLC, GC-MS, study of antimicrobial activity in vitro.Results and discussion. Based on the results of a literature search, 3 promising substances were selected for the development of a multicomponent plant-based substance: tea tree essential oil, 1,8-cineole and α-(-)-bisabolol. Molecular docking predicted the targeted activity of the phytochemicals of tea tree essential oil, 1,8-cineole and α-(-)-bisabolol on the domains of ABC-transporters of microorganisms involved in the pathogenesis of seborrheic dermatitis and justified the possibility of use for therapy. The multicomponent substance has been developed based on tea tree essential oil, 1,8-cineole and α-(-)-bisabolol in a mass ratio of 1 : 1 : 1. The qualitative composition of the substance was assessed by TLC and GC-MS methods, and 15 terpenes were quantitatively identified in its composition with a predominance of terpinen-4-ol (16.98 %), 1,8-cineole (25.63 %) and α-(-)-bisabolol (27.67 %). The synergistic antimicrobial activity of the substance has been established against S. epidermidis, S. aureus, C. albicans and M. furfur in comparison with benzalkonium chloride, ketoconazole and climbazole. The composition of a new medical shampoo based on the investigated substance has been developed, which has a pronounced antifungal effect (more than 99.0 %) against M. furfur without visible suppression of normal microflora. For the novel substance of plant origin and medical shampoo, quality parameters were assessed in accordance with the Russian Pharmacopoeia of XIV edition.Conclusion. A substance of plant origin with synergistic and targeted antimicrobial activity has been developed. It has an interest for further study as a drug and API for new products for the treatment of seborrheic dermatitis.

Hybrid Machine Learning and Experimental Studies of Antiviral Potential of Ionic Liquids against P100, MS2, and Phi6.

Viruses are a group of widespread organisms that are often responsible for very dangerous diseases, as most of them follow a mechanism to multiply and infect their hosts as quickly as possible. Pathogen viruses also mutate regularly, with the result that measures to prevent virus transmission and recover from the disease caused are often limited. The development of new substances is very time-consuming and highly budgeted and requires the sacrifice of many living organisms. Computational chemistry methods allow faster analysis at a much lower cost and, most importantly, reduce the number of living organisms sacrificed experimentally to a minimum. Ionic liquids (ILs) are a group of chemical compounds that could potentially find a wide range of applications due to their potential virucidal activity. In our study, we conducted a complex computational analysis to predict the antiviral activity of ionic liquids against three surrogate viruses: two nonenveloped viruses, Listeria monocytogenes phage P100 and Escherichia coli phage MS2, and one enveloped virus, Pseudomonas syringae phage Phi6. Based on experimental data of toxic activity (logEC90), we assigned activity classes to 154 ILs. Prediction models were created and validated according to the Organization for Economic Co-operation and Development (OECD) recommendations using the Classification Tree method. Further, we performed an external validation of our models through virtual screening on a set of 1277 theoretically generated ionic liquids and then selected 10 active ionic liquids, which were synthesized to verify their activity against the analyzed viruses. Our study proved the effectiveness and efficiency of computational methods to predict the antiviral activity of ionic liquids. Thus, computational models are a cost-effective alternative approach compared with time-consuming experimental studies where live animals are involved.

ADMET and Solubility Analysis of New 5-Nitroisatine-Based Inhibitors of CDK2 Enzymes.

The development of new substances with the ability to interact with a biological target is only the first stage in the process of the creation of new drugs. The 5-nitroisatin derivatives considered in this study are new inhibitors of cyclin-dependent kinase 2 (CDK2) intended for anticancer therapy. The research, carried out based on the ADMET (absorption, distribution, metabolism, excretion, toxicity) methods, allowed a basic assessment of the physicochemical parameters of the tested drugs to be made. The collected data clearly showed the good oral absorption, membrane permeability, and bioavailability of the tested substances. The analysis of the metabolite activity and toxicity of the tested drugs did not show any critical hazards in terms of the toxicity of the tested substances. The substances' low solubility in water meant that extended studies tested compounds were required, which helped to select solvents with a high dissolving capacity of the examined substances, such as DMSO or NMP. The use of aqueous binary mixtures based on these two solvents allowed a relatively high solubility with significantly reduced toxicity and environmental index compared to pure solvents to be maintained, which is important in the context of the search for green solvents for pharmaceutical use.

Antibiofilm assay for antimicrobial peptides combating the sulfate-reducing bacteria Desulfovibrio vulgaris.

In medical, environmental, and industrial processes, the accumulation of bacteria in biofilms can disrupt many processes. Antimicrobial peptides (AMPs) are receiving increasing attention in the development of new substances to avoid or reduce biofilm formation. There is a lack of parallel testing of the effect against biofilms in this area, as well as in the testing of other antibiofilm agents. In this paper, a high-throughput screening was developed for the analysis of the antibiofilm activity of AMPs, differentiated into inhibition and removal of a biofilm. The sulfate-reducing bacterium Desulfovibrio vulgaris was used as a model organism.D. vulgaris represents an undesirable bacterium, which is considered one of the major triggers of microbiologically influenced corrosion. The application of a 96-well plate and steel rivets as a growth surface realizes real-life conditions and at the same time establishes a flexible, simple, fast, and cost-effective assay. All peptides tested in this study demonstrated antibiofilm activity, although these peptides should be individually selected depending on the addressed aim. For biofilm inhibition, the peptide DASamP1 is the most suitable, with a sustained effect for up to 21 days. The preferred peptides for biofilm removal are S6L3-33, in regard to bacteria reduction, and Bactenecin, regarding total biomass reduction.

CK2 and protein kinases of the CK1 superfamily as targets for neurodegenerative disorders.

Casein kinases are involved in a variety of signaling pathways, and also in inflammation, cancer, and neurological diseases. Therefore, they are regarded as potential therapeutic targets for drug design. Recent studies have highlighted the importance of the casein kinase 1 superfamily as well as protein kinase CK2 in the development of several neurodegenerative pathologies, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. CK1 kinases and their closely related tau tubulin kinases as well as CK2 are found to be overexpressed in the mammalian brain. Numerous substrates have been detected which play crucial roles in neuronal and synaptic network functions and activities. The development of new substances for the treatment of these pathologies is in high demand. The impact of these kinases in the progress of neurodegenerative disorders, their bona fide substrates, and numerous natural and synthetic compounds which are able to inhibit CK1, TTBK, and CK2 are discussed in this review.

The Current Role of Peptide Receptor Radionuclide Therapy in Meningiomas.

Meningiomas are the most common primary intracranial tumors. The majority of patients can be cured by surgery, or tumor growth can be stabilized by radiation. However, the management of recurrent and more aggressive tumors remains difficult because no established alternative treatment options exist. Therefore, innovative therapeutic approaches are needed. Studies have shown that meningiomas express somatostatin receptors. It is well known from treating neuroendocrine tumors that peptide radioreceptor therapy that targets somatostatin receptors can be effective. As yet, this therapy has been used for treating meningiomas only within individual curative trials. However, small case series and studies have demonstrated stabilization of the disease. Therefore, we see potential for optimizing this therapeutic option through the development of new substances and specific adaptations to the different meningioma subtypes. The current review provides an overview of this topic.

Molecular Hydrogen as a Medical Gas for the Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Possible Efficacy Based on a Literature Review.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disorder that is characterized by fatigue that persists for more than 6 months, weakness, sleep disturbances, and cognitive dysfunction. There are multiple possible etiologies for ME/CFS, among which mitochondrial dysfunction plays a major role in abnormal energy metabolism. The potential of many substances for the treatment of ME/CFS has been examined; however, satisfactory outcomes have not yet been achieved. The development of new substances for curative, not symptomatic, treatments is desired. Molecular hydrogen (H2) ameliorates mitochondrial dysfunction by scavenging hydroxyl radicals, the most potent oxidant among reactive oxygen species. Animal experiments and clinical trials reported that H2 exerted ameliorative effects on acute and chronic fatigue. Therefore, we conducted a literature review on the mechanism by which H2 improves acute and chronic fatigue in animals and healthy people and showed that the attenuation of mitochondrial dysfunction by H2 may be involved in the ameliorative effects. Although further clinical trials are needed to determine the efficacy and mechanism of H2 gas in ME/CFS, our literature review suggested that H2 gas may be an effective medical gas for the treatment of ME/CFS.

Актуальні питання запобігання насильницьким злочинам в установах виконання покарань

The author notes in the article that security in penal institutions consists of three components: physical, procedural and dynamic security. All three components play an important role in preventing violence in penal institutions. The author points out the main directions of improving the security components in penal institutions and identifies the main problems that arise in the activities of law enforcement officers and which are related to the prevention of violent criminal offenses. The author notes that today in the world there are so-called “synthetic drugs”, which must be included to a special list. The practice of combating drug addiction indicates that the procedure for amending this list is quite bureaucratic and does not keep up with the development of new substances. An expert, in turn, conducting an expert research, can’t recognize a substance that is not in this list of drugs. This fact makes it impossible to bring a perpetrator to justice. The article states that another problematic issue in the activities related to the prevention of violent crimes in penal institutions is the fact that convicts possess assault weapons. Bringing them to justice under Art. 263 of the Criminal Code of Ukraine (Illegal handling of the weapon, ammunition or explosives) for carrying, manufacturing, repair or sale of daggers, Finnish knives, knuckles or other cold-arms without the permission provided by the law is possible only after the conclusion of an expert. Such a conclusion must contain the information that the assault weapon seized from a convict is a cold-arms. Very often, items used by convicts as weapons in order to attack, although outwardly meet the requirements for cold-arms, but do not pass these rather severe static and dynamic tests. Key words: criminal offenses, violent crime, penal institution, prohibited items, convict.

Endophytic fungi: Benefits for plants and biotechnological potential

Endophytic fungi are microorganisms that live inside plants, establishing a mutualistic relationship, where both benefit from this interaction. They require protection and nutrients from host plants, and in return fungi can contribute to host's growth and nutrient uptake. In addition, they can improve plant tolerance to abiotic and biotic stresses and increase plant resistance to insects and pests. Endophytic fungi produce bioactive compounds similar to those of the host plant. The economic exploitation of these bioactive compounds is much promising. These bioactive products are related to sustainable production systems and to the development of new substances with strong pharmacological properties such as antiviral, antifungal, anti-inflammatory, antitumor and antiparasitic, antidiabetic and immunosuppressant, including response to resistant microorganisms. This study is a descriptive review, having as aim to approach the main benefits of endophytic fungi for host plants, as well as the biotechnological application of the bioactive compounds produced by them. The prospection of endophytic in extreme environment could result in discovery of new bioactive compounds with surprising potential for biotechnology area. So, the development of new research frontiers in this issue is indispensable for the sustainable exploitation of the great benefits that these microorganisms could provide to the science.

In search of the Holy Grail of Rodent control: Step-by-step implementation of safe and sustainable-by-design principles on the example of rodenticides

The field of chemical rodent control has seen no major developments in the last decades, even though anticoagulant rodenticides (AR), the mainly used substances to manage mice and rats, are known environmental pollutants and candidates for substitution under the European Biocidal Products Regulation 528/2012. Moreover, recent political developments in Europe and the USA demand more safety and sustainability in the management of chemicals, reinforcing the need for environmentally friendly substances. In this concept study, we present a step-by-step approach to improve the environmental properties of rodenticides. Repurposing of existing pharmaceuticals, the use of enantiomerically pure rodenticides, or the improvement of the formulation by microencapsulation can help to alleviate environmental problems caused by AR in the short term. Modification of the chemical structures or the development of prodrugs as medium-term strategies can further improve environmental properties of existing compounds. Ultimately, the development of new substances from scratch enables the utilisation of so far ignored modes of actions and the application of modern safe and sustainable-by-design principles to improve target specificity and reduce the negative impact on non-target organisms and the environment. Overall, our concept study illustrates the great potential for improvement in the field of chemical rodent control when applying available techniques of green and sustainable chemistry to known or potential rodenticides. Most promising in the medium term is microencapsulation that would allow for the use of acutely acting substances as it could circumvent bait shyness. On a longer timescale the de novo design of new rodenticides, which is the only method that can combine a high target specificity with good environmental properties, is the most promising approach.

A second generation of 1,2,4-oxadiazole derivatives with enhanced solubility for inhibition of 3-hydroxykynurenine transaminase (HKT) from Aedes aegypti.

The most widely used method for the control of the Aedes aegypti mosquito population is the chemical control method. It represents a time- and cost-effective way to curb several diseases (e.g. dengue, Zika, chikungunya, yellow fever) through vector control. For this reason, the discovery of new compounds with a distinct mode of action from the available ones is essential in order to minimize the rise of insecticide resistance. Detoxification enzymes are an attractive target for the discovery of new insecticides. The kynurenine pathway is an important metabolic pathway, and it leads to the chemically stable xanthurenic acid, biosynthesized from 3-hydroxykynurenine, a precursor of reactive oxygen and nitrogen species, by the enzyme 3-hydroxykynurenine transaminase (HKT). Previously, we have reported the effectiveness of 1,2,4-oxadiazole derivatives acting as larvicides for A. aegypti and AeHKT inhibitors from in vitro and in silico studies. Here, we report the synthesis of new sodium 4-[3-(aryl)-1,2,4-oxadiazol-5-yl] propanoates and the cognate HKT-inhibitory activity. These new derivatives act as competitive inhibitors with IC50 values in the range of 42 to 339 μM. We further performed molecular docking simulations and QSAR analysis for the previously synthesized sodium 4-[3-(aryl)-1,2,4-oxadiazol-5-yl] butanoates reported earlier by our group and the data produced herein. Most of the 1,2,4-oxadiazole derivatives, including the canonical compounds for both series, showed a similar binding mode with HKT. The binding occurs similarly to the co-crystallized inhibitor via anchoring to Arg356 and positioning of the aromatic ring and its substituents outwards at the entry of the active site. QSAR analysis was performed in search of more than 770 molecular descriptors to establish a relationship between the lowest energy conformations and the IC50 values. The five best descriptors were selected to create and validate the model, which exhibited parameters that attested to its robustness and predictability. In summary, we observed that compounds with a para substitution and heavier groups (i.e. CF3 and NO2 substituents) had an enhanced HKT-inhibition profile. These compounds comprise a series described as AeHKT inhibitors via enzymatic inhibition experiments, opening the way to further the development of new substances with higher potency against HKT from Aedes aegypti.

Advances in Molecular Imaging and Radionuclide Therapy of Neuroendocrine Tumors.

Neuroendocrine neoplasms make up a heterogeneous group of tumors with inter-patient and intra-patient variabilities. Molecular imaging can help to identify and characterize neuroendocrine tumors (NETs). Furthermore, imaging and treatment with novel theranostics agents offers a new, tailored approach to managing NETs. Recent advances in the management of NETs aim to enhance the effectiveness of targeted treatment with either modifications of known substances or the development of new substances with better targeting features. There have been several attempts to increase the detectability of NET lesions via positron emission tomography (PET) imaging and improvements in pretreatment planning using dosimetry. Especially notable is PET imaging with the radionuclide Copper-64. Increasing interest is also being paid to theranostics of grade 3 and purely differentiated NETs, for example, via targeting of the C-X-C motif chemokine receptor 4 (CXCR4). The aim of this review is to summarize the most relevant recent studies, which present promising new agents in molecular imaging and therapy for NETs, novel combination therapies and new applications of existing molecular imaging modalities in nuclear medicine.

Study of the Mechanism of the Antimicrobial Activity of Novel Water Soluble Ammonium Quaternary Benzanthrone on Model Membranes.

The increasing resistance of many pathogens to most of the common antimicrobials requires the development of new substances with more effective antimicrobial properties. In the present work, we investigated the mechanism of the antimicrobial activity of novel water soluble ammonium quaternary benzanthrone (Compound B) on model membranes, composed of dipalmitoylphosphatidylcholine, 1-palmitoyl-2-oleoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, 1-palmitoyl-2-oleoylphosphatidylglycerol, and dipalmitoylphosphatidylethanolamine (DPPE). The lipids were chosen to represent a model of a bacterial membrane. The changes in surface pressure of the model membranes, before and after the addition of Compound B, were studied by the Langmuir's monolayer method, and the compressional modulus for each monolayer was determined. In addition, the surface morphology of the lipid monolayers before and after injection of Compound B was monitored by Brewster Angle Microscopy. The results showed that Compound B penetrated all the monolayers studied. The most noticeable effects were found with the negatively charged phosphatidylglycerols and with DPPE leading to the conclusion that the electrostatic interactions between the compound and the lipid head groups and the possible formation of hydrogen bonds between the amino group of the ethanolamine and the keto groups in the structure of Compound B are of great importance. In addition, the penetration ability of the benzoquinone with all phospholipids studied was stable even at higher values of the surface pressure, i.e. thicker monolayers, due to the hydrophobic interaction, which plays also an important role for the antimicrobial activity of Compound B.

Exosomes in Inflammatory Bowel Disease: What Have We Learned So Far?

Inflammatory bowel disease (IBD) is an immune-mediated chronic inflammatory disease. Although the etiology is uncertain, there is marked disbalance of mucosal immune responses in part shaped by genetic susceptibility and intestinal microbial dysbiosis. Suppressing inflammatory activity adequately and maintaining this suppression are the main goals of current therapies. However, corticosteroids are only suitable for therapy of active disease, and the effects of immunosuppressive agents are mainly limited to maintenance of remission. Biologics have become widely available and provide therapeutic benefits to IBD patients. However, only a part of patients benefits from them. Thus, there is an urgent need for the development of new substances in the therapy of IBD. Exosomes are nanosized lipid vesicles identified recently. They are secreted from all living cells and then distributed in various human body fluids. The components, such as microRNAs and functional proteins, secreted by exosomes in different cells have been reported to be involved in the pathogenesis of IBD. Therefore, exosomes have the potential to become appealing particles in treating IBD as a cell-free therapeutic approach as well as biomarkers for diagnosis and monitoring disease status. Further studies are needed to investigate the practicality, safety and desirable effects of exosomes in clinical applications in IBD.

Computational aided acetaminophen – phthalic acid molecularly imprinted polymer design for analytical determination of known and new developed recreational drugs

In recent times, abuse drug consumption rates have been increasing. In addition, authorities have detected a trend in the development of new substances expressly created to avoid legislation. These novel psychoactive substances (NPS) are non-registered formulations, closely chemically related to outlawed ones to maintain the same psychotropic effects while circumventing legal restrictions.This issue arises enormous social, sanitary, and road safety problems since there is no way to detect nor quantify these non-registered substances.The aim of this work is the development of a high selective material able to pre-concentrate and detect NPS. On that account, molecularly imprinted polymers (MIPs) designed with an imprinted cavity that matches the cathinones structural shape were proposed to detect both conventional and new cathinone derived recreational drugs.The increasing number of illicit drug modifications that is being reported requires developing a receptor valid for not only known molecules but also for incoming ones; thus, a virtual procedure must be carried out to take a step forward towards future modifications. Accordingly, a computational MIP design is proposed as the most appropriated method to effectively design this receptor.By means of molecular dynamics and molecular docking, several combinations are studied regarding their pre-polymerization complex stability but also their rebinding capacity against the proposed analytes.Hence, a phthalic acid – acetaminophen MIP is selected as the most well-suited receptor, valid for current and forthcoming cathinone recreational drugs.

Cryoprotective Properties of the Polysaccharide Fraction of the Mushroom Hericium erinaceus BP 16

The natural isolate of xylotrophic basidiomycetes Hericium erinaceus BP 16 was cultivated artificially to produce fruiting bodies from which the polysaccharide-containing fraction (PF) was isolated by extraction with hot water (70°C), followed by precipitation with 96% ethanol. Residues of rhamnose, fructose, xylose, arabinose, mannose, glucose, and galactose in the ratio of 7 : 8 : 1 : 19 : 14 : 26 : 27, respectively, were identified in the composition of the PF carbohydrate chains. The effect of adding PF to aqueous solutions of cryoprotectants during water freezing in human venous blood during its cryopreservation has been demonstrated. It was found that the presence of PF (0.25%) in a glycerin-containing (3.5%) preservative ensures the safety of human nuclear blood cells at −20 and −80°C, which indicated the cryoprotective activity of PF H. erinaceus BP 16. Thus, this property of PF may be used in the development of new substances to freeze biological samples.

Antibiofilm Potential of Arenecarbaldehyde 2-Pyridinylhydrazone Derivatives Against Acinetobacter baumannii.

In the last 15 years, Acinetobacter baumannii has received special attention, mainly due to several resistance mechanisms and high rates of morbimortality. The ability to form biofilms contributes to the persistence of this microorganism in the hospital environment and facilitates the occurrence of nosocomial infections. Several studies have highlighted the pharmacological relevance of pyridines in the treatment and control of infectious diseases and others have related the anti-A. baumannii potential of hydrazine derivatives. Considering this scenario, we aimed to evaluate the antimicrobial and antibiofilm activity of 10 pyridinylhydrazone compounds against A. baumannii. The minimum inhibitory concentration of the compounds was determined by broth microdilution method and the antibiofilm activity was evaluated by inhibition and destruction biofilm assays. In addition, the cytotoxicity of the compounds in the J774A.1 cell line was also evaluated, and the selectivity index was calculated. Among the 10 pyridine compounds, the compounds B and D were able to inhibit the formation of biofilms and destroy bacterial biofilms even in a concentration of 12.5 μg/mL. Thus, the pyridine compounds evaluated can be a scaffold for the development of new substances with antimicrobial and antibiofilm activity.

In Silico Identification of Potential Inhibitors of the Wnt Signaling Pathway in Human Breast Cancer.

Triple-negative breast cancer is the leading worldwide cause of cancer-related deaths in women. The prospection and development of new substances with antitumoral potential is of great importance for the treatment of this disease. The objective of this work was to identify a commercial drug or ligand that could potentially bind to the FZD7 transmembrane protein and inactivate the Wnt signaling pathway in triple-negative breast cancer cells. We aimed at computationally modeling the FZD7, Wnt3, and Wnt3a proteins, at making them available in protein model databases, and at conducting docking analysis to assess the binding free energy between FZD7 and the selected ligands. The Wnt3 and Wnt3a proteins were modeled by homology modeling, and the FZD7 protein was modeled by homology modeling and ab initio modeling. The ligands were selected based on their similarity to the palmitoleic acid and were gathered from the ZINC database. A total of 30 commercially available ligands were found in the ZINC database. The docking results show that the ligands zinc08221009, zinc13546050, zinc05260769, zinc04529321, and zinc05972969 are good candidates for novel drug development. The created models and conducted analysis by this work will most certainly help in future research on the Wnt signaling pathway and its components.

New antibiotics for severe infections due to multidrug-resistant pathogens : Definitive treatment and escalation

Multidrug-resistant pathogens often lead to treatment failure of antimicrobial regimens. After a period of imbalance between the occurrence/spread of resistance mechanisms and the development of new substances, some new substances have meanwhile been approved and many more are currently undergoing clinical testing. They are particularly effective against specific resistance mechanisms/pathogens and should be preserved for definitive treatment of an isolated pathogen. In the absence of alternatives reserve antibiotics, such as aztreonam and colistin have experienced a renaissance. They are again used in special infection scenarios and clinically tested in combination with new substances. Despite the introduction and development of new substances the building of resistance will at some time also render these (at least partially) ineffective. Therefore, their implementation must be carried out according to the antibiotic or infectious diseases stewardship.