Tomasz Frączek

Assessing Molecular Docking Tools for Relative Biological Activity Prediction: A Case Study of Triazole HIV-1 NNRTIs

Molecular docking is a technique widely used in drug design. Many studies exist regarding the general accuracy of various docking programs, but case studies for a given group of related compounds are rare. In order to facilitate identification of novel triazole HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), several docking and scoring programs were evaluated for their ability to predict relative biological activity of 111 known 1,2,4-triazole and 76 other azole type NNRTIs. Glide, FlexX, Molegro Virtual Docker, AutoDock Vina, and Hyde were used. Different protocols, settings, scoring functions, and interaction terms were analyzed. We have found that the programs performance was dependent on the data set, indicating the importance of choosing good quality target data for any comparative study. The results suggest that after optimization and proper validation, some of the molecular docking programs can help in predicting relative biological activity of azole NNRTIs.

Mercury in the eggs of aquatic birds from the Gulf of Gdansk and Wloclawek Dam (Poland).

The aim of this paper was to assess the influence of diet on the concentrations of total mercury (HgTOT) in the eggs of aquatic birds. Trophic level was determined using stable isotopes (δ15N, δ13C). Analysis was carried out on eggs (laid in 2010–2012) belonging to two species of terns nesting at the River Vistula outlet on the Gulf of Gdansk and on herring gulls nesting both in Gdynia harbour and on the Vistula dam in Wloclawek. The results show that seafood diet causes the highest load of mercury, that which is transferred into terns eggs. The amounts of accumulated mercury obtained were found to be different in the particular egg components with Hgalbumen > Hgyolk > Hgmembrane > Hgshell. In the herring gull eggs, three stages of embryo development with varying levels of mercury were determined. It was observed that mercury received from the albumen and yolk was most effectively removed when developing embryo into down.

Searching for novel scaffold of triazole non-nucleoside inhibitors of HIV-1 reverse transcriptase

Abstract Azoles are a promising class of the new generation of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). From thousands of reported compounds, many possess the same basic structure of an aryl substituted azole ring linked by a thioglycolamide chain with another aromatic ring. In order to find novel extensions for this basic scaffold, we explored the 5-position substitution pattern of triazole NNRTIs using molecular docking followed by the synthesis of selected compounds. We found that heterocyclic substituents in the 5-position of the triazole ring are detrimental to the inhibitory activity of compounds with four-membered thioglycolamide linker and this substitution seems to be viable only for compounds with shorter two-membered linker. Promising compound, N-(4-carboxy-2-chlorophenyl)-2-((4-benzyl-5-methyl-4H-1,2,4-triazol-3-yl)sulfanyl)acetamide, with potent inhibitory activity and acceptable aqueous solubility has been identified in this study that could serve as lead scaffold for the development of novel water-soluble salts of triazole NNRTIs.

Diaryl ethers with carboxymethoxyphenacyl motif as potent HIV-1 reverse transcriptase inhibitors with improved solubility

Abstract In search of new non-nucleoside reverse transcriptase inhibitors (NNRTIs) with improved solubility, two series of novel diaryl ethers with phenacyl moiety were designed and evaluated for their HIV-1 reverse transcriptase inhibition potentials. All compounds exhibited good to excellent results with IC50 at low micromolar to submicromolar concentrations. Two most active compounds (7e and 7 g) exhibit inhibitory potency comparable or even better than that of nevirapine and rilpivirine. Furthermore, SupT1 and CD4+ cell infectivity assays for the most promising (7e) have confirmed its strong antiviral potential while docking studies indicate a novel binding interactions responsible for high activity. Graphical Abstract

A Search for Dual Action HIV-1 Reverse Transcriptase, Bacterial RNA Polymerase Inhibitors

Using molecular modeling approach, potential antibacterial agents with triazole core were proposed. A moderate to weak level of antibacterial activity in most of the compounds have been observed, with best minimal inhibitory concentration (MIC) value of 0.003 mg/mL, as shown by the 15 against S. epidermidis. Studied compounds were also submitted to the antifungal assay. The best antifungal activity was detected for 16 with MIC at 0.125 and 0.25 mg/mL against C. albicans and C. parapsilosis, respectively.

Hepatoblastoma Biology Using Isotope Ratio Mass Spectrometry: Utility of a Unique Technique for the Analysis of Oncological Specimens

INTRODUCTION Hepatoblastoma is the most common primary liver tumor in children. However, it occurs rarely, with an incidence of 0.5-1.5 cases per million children. There is no clear explanation of the relationship between clinicopathologic features, therapy, and outcome in hepatoblastoma cases, so far. One of the most widely accepted prognostic factors in hepatoblastoma is histology of the tumor. The aim of the study was to determine the potential differences in biology of hepatoblastoma histological subtypes at the atomic level using the unique method of isotope ratio mass spectrometry, which is especially valuable in examination of small groups of biological samples. MATERIAL/METHODS Twenty-four measurements of nitrogen stable isotope ratio, carbon stable isotope ratio and total carbon to nitrogen mass ratio in fetal and embryonal hepatoblastoma tissue were performed using a Sercon 20-22 Continuous Flow Isotope Ratio Mass Spectrometer (CF-IRMS) coupled with a Sercon SL elemental analyzer for simultaneous carbon-nitrogen-sulfur (NCS) analysis. RESULTS A difference of about 1.781‰ in stable nitrogen isotope 15N/14N ratio was found between examined hepatoblastoma histological subtypes. CONCLUSIONS The prognosis in liver tumors cases in children may be challenging particularly because of the lack of versatile methods of its evaluation. Isotope ratio mass spectrometry allows one to determine the difference between hepatoblastoma histological subtypes and clearly indicates the cases with the best outcome.

Simulation-Based Algorithm for Two-Dimensional Chemical Structure Diagram Generation of Complex Molecules and Ligand–Protein Interactions

Computer programs for structure diagram generation (SDG) are indispensable cheminformatic tools that translate one- or three-dimensional (1D or 3D) chemical structure data stored in electronic formats to human-readable 2D depictions. Although many such programs are known, only a moderate part of chemical space can be handled by existing algorithms. For many classes of natural and synthetic compounds the results obtained with current SDG methods are illegible. A new algorithm based solely on a physical simulation of a molecule has been developed. The method allows for a general and global approach to avoid overlapping atoms and substituents. While the algorithm shows no advantage for trivial molecules, it shows superior performance over existing methods in depicting the most challenging compounds. The algorithm can generate chemically correct and legible 2D structure diagrams of many classes of natural and synthetic compounds that are intractable with existing SDG algorithms. The use of the method for generating schematic ligand-receptor interaction diagrams is also discussed.