Chemical investigation of drug-like compounds from the Australian tree,Neolitsea dealbata

Two of the four parameters in the ‘rule of five’, molecular weight and log P, which can be detected and predicted by mass spectrometry and compound retention on reversed-phase HPLC, were used as guidelines in natural product isolation. A new aporphine alkaloid, (6aR)-normecambroline (1), was isolated from the bark of Neolitsea dealbata (R. Br.) Merr. Its structure was determined on the basis of NMR, MS and CD analysis. It is the first time the absolute configuration of the roemerine-N-oxide was assigned for both roemerine-N_α-oxide (3) and roemerine-N_β-oxide (4). Physico-chemical property evaluation demonstrated all alkaloids had no Lipinski violation. Compound 1 inhibited selectively against cervical cancer cells (HeLa) with an IC₅₀ of 4.0 μM.     

Release of 50 new,drug-like compounds and their computational target predictions for open source anti-tubercular drug discovery

As a follow up to the antimycobacterial screening exercise and the release of GSK´s first Tres Cantos Antimycobacterial Set (TCAMS-TB), this paper presents the results of a second antitubercular screening effort of two hundred and fifty thousand compounds recently added to the GSK collection. The compounds were further prioritized based on not only antitubercular potency but also on physicochemical characteristics. The 50 most attractive compounds were then progressed for evaluation in three different predictive computational biology algorithms based on structural similarity or GSK historical biological assay data in order to determine their possible mechanisms of action. This effort has resulted in the identification of novel compounds and their hypothesized targets that will hopefully fuel future TB drug discovery and target validation programs alike.     

Effect of reaction media concentration on the solubility and the chemical structure of lignin model compounds

In plant cell walls, lignin polymerization occurs in concentrated polysaccharide gel. The effect of high polysaccharide concentrations on the structure of lignin-like polymers (DHPs=dehydrogenation polymers), were investigated by running lignification-like polymerization under three reaction conditions in which the concentrations of all reactants (xylan/coniferyl alcohol (CA)/oxidising system) were gradually increased. Control experiments were also run in similar conditions but without polysaccharides. DHPs showed increased solubility with increased concentrations of reactants in the presence of xylans but were mostly insoluble in buffer control experiments. The structures of DHPs were characterized by thioacidolysis and size exclusion chromatography (SEC). Results indicated that the frequency of beta-alkyl aryl ether bonds and DHP molecular weight increased with increasing concentration of the reaction mixture in the presence of xylans whereas those of control DHPs decreased slightly under the same conditions. This emphasizes the role of the pre-existing polysaccharide gel and high concentrations existing in the cell wall during construction of the lignin polymer.     

QSAR-based prediction of anti-HCV activity of thiourea derivatives

Quantitative structure–activity relationship (QSAR) studies were performed on a series of thioureas to explore the physico-chemical parameters responsible for their activity against the hepatitis C virus (HCV)-infected AVa5 cell. The physico-chemical parameters were calculated using WIN CAChe 6.1. Multiple linear regression analysis, after the variables selection by factor analysis, was performed to derive QSAR models which were further evaluated for their statistical significance and predictive power by internal and external validation. The developed QSAR model had the correlation coefficient (R) = 0.928 and cross-validated squared correlation coefficient (Q ²) = 0.751. The selected significant QSAR model indicates that hydrophobicity, dielectric energy, valence connectivity index (order 1), conformational minimum energy and highest occupied molecular orbital of the whole molecule play an important role in the anti-HCV activity of thioureas.     

High throughput solubility determination with application to selection of compounds for fragment screening

The development and application of a high throughput aqueous solubility assay is reported. Measurements for up to 637 compounds can be made in a fully automated experiment. Results from this assay were used to quantify risk of unacceptable solubility as a function of lipophilicity for neutral fragment-like compounds. Assessment of risk of unacceptable solubility was combined with experimental solubility measurement to select compounds for inclusion in a fragment-screening library.     

Antimutagenicity profiles for some model compounds

The concept of activity profile listings and plots, already applied successfully to the display of mutagenicity data, has been modified for application to antimutagenicity data. The activity profiles are bar graphs that have been organized in two general ways: for antimutagens that have been tested in combination with a given mutagen and for mutagens that have been tested in combination with a given antimutagen. Doses from both the mutagen and the antimutagen are displayed and plotted together with results on enhancement or inhibition of mutagenic activity. The short-term tests that have been used extensively to identify mutagens and potential carcinogens are increasingly being used to identify antimutagens and potential anticarcinogens. Three model mutagens, N-methyl-N'-nitro-N-nitrosoguanidine, aflatoxin B1 and benzo[a]pyrene, and 4 model antimutagens, butylated hydroxyanisole, butylated hydroxytoluene, glutathione and disulfiram, were selected from the data surveyed in the published literature. It is not clear at the present time whether the inhibition of carcinogen-induced mutation is a good indicator of anticarcinogenic properties, and further research is needed. Nevertheless, the activity profiles are useful for the assessment of the available antimutagenesis data by providing rapid visualization of considerable dose information and experimental results.     

Tyrosine kinase syk non-enzymatic inhibitors and potential anti-allergic drug-like compounds discovered by virtual and in vitro screening

In the past decade, the spleen tyrosine kinase (Syk) has shown a high potential for the discovery of new treatments for inflammatory and autoimmune disorders. Pharmacological inhibitors of Syk catalytic site bearing therapeutic potential have been developed, with however limited specificity towards Syk. To address this topic, we opted for the design of drug-like compounds that could impede the interaction of Syk with its cellular partners while maintaining an active kinase protein. To achieve this challenging task, we used the powerful potential of intracellular antibodies for the modulation of cellular functions in vivo, combined to structure-based in silico screening. In our previous studies, we reported the anti-allergic properties of the intracellular antibody G4G11. With the aim of finding functional mimics of G4G11, we developed an Antibody Displacement Assay and we isolated the drug-like compound C-13, with promising in vivo anti-allergic activity. The likely binding cavity of this compound is located at the close vicinity of G4G11 epitope, far away from the catalytic site of Syk. Here we report the virtual screen of a collection of 500,000 molecules against this new cavity, which led to the isolation of 1000 compounds subsequently evaluated for their in vitro inhibitory effects using the Antibody Displacement Assay. Eighty five compounds were selected and evaluated for their ability to inhibit the liberation of allergic mediators from mast cells. Among them, 10 compounds inhibited degranulation with IC₅₀ values ≤10 µM. The most bioactive compounds combine biological activity, significant inhibition of antibody binding and strong affinity for Syk. Moreover, these molecules show a good potential for oral bioavailability and are not kinase catalytic site inhibitors. These bioactive compounds could be used as starting points for the development of new classes of non-enzymatic inhibitors of Syk and for drug discovery endeavour in the field of inflammation related disorders.     

Role of dissolution rate and solubility in biodegradation of aromatic compounds

[This corrects the article on p. 294 in vol. 53.].     

Role of dissolution rate and solubility in biodegradation of aromatic compounds

Strains of Moraxella sp., Pseudomonas sp., and Flavobacterium sp. able to grow on biphenyl were isolated from sewage. The bacteria produced 2.3 to 4.5 g of protein per mol of biphenyl carbon, and similar protein yields were obtained when the isolates were grown on succinate. Mineralization of biphenyl was exponential during the phase of exponential growth of Moraxella sp. and Pseudomonas sp. In biphenyl-supplemented media, Flavobacterium sp. had one exponential phase of growth apparently at the expense of contaminating dissolved carbon in the solution and a second exponential phase during which it mineralized the hydrocarbon. Phase-contrast microscopy did not show significant numbers of cells of these three species on the surface of the solid substrate as it underwent decomposition. Pseudomonas sp. did not form products that affected the solubility of biphenyl, although its excretions did increase the dissolution rate. It was calculated that Pseudomonas sp. consumed 29 nmol of biphenyl per ml in the 1 h after the end of the exponential phase of growth, but 32 nmol of substrate per ml went into solution in that period when the growth rate had declined. In a medium with anthracene as the sole added carbon source, Flavobacterium sp. converted 90% of the substrate to water-soluble products, and a slow mineralization was detected when the cell numbers were not increasing. Flavobacterium sp. and Beijerinckia sp. initially grew exponentially and then arithmetically in media with phenanthrene as the sole carbon source. Calculations based on the growth rates of these bacteria and the rates of dissolution of phenanthrene suggest that the dissolution rate of the hydrocarbon may limit the rate of its biodegradation.     

Recognizing molecules with drug-like properties.

A variety of successful approaches to the problem of recognizing 'drug-like' molecules have been employed. These range from simple counting schemes such as the Lipinski 'rule of five' to the analysis of the multidimensional 'chemistry space' occupied by drugs, to neural network learning systems. With this variety of tools, it now appears possible to design libraries that are enriched in compounds which have desirable or 'drug-like' properties. Verifying the robustness of these methods, and extending them, will form the basis of research in this field during the next few years.     

Profiling drug-like properties in discovery research

Measurement and application of compound properties for candidate selection and optimization is an emerging trend. Property-based design supplements successful activity-based strategies to produce drug-like candidates. High-throughput screening hits are evaluated for integrity and aggregation to ensure quality leads. Solubility data assures accurate activity assays and predicts absorbance. Cellular and artificial membrane permeability assays indicate compound penetration through membranes in cells, intestine and blood-brain barrier. Lipophilicity and pK(a) provide fundamental structure design elements. Stability in liver, plasma and buffer evaluates compound lifetime. Drug-drug interaction is predicted using CYP inhibition assays. Drug-like properties are vital to successful drug candidates and enhance drug discovery.     

Influence of pectins on the solubility and the molar mass distribution of dehydrogenative polymers (DHPs, lignin model compounds).

Dehydrogenation polymers (DHPs, lignin model compounds) were synthesized in the presence of increasing pectin concentrations using two different methods. The first method ('Zutropfverfahren', ZT) consists in the slow adding of monomers whereas in the second method ('Zulaufverfahren', ZL) all the reactants are added simultaneously. DHPs solubility increases with the pectin concentration in the ZT experiments and remains stable in the ZL experiments. Covalent bonds between pectin and DHP are formed during ZT polymerization resulting in lignin carbohydrate complex (LCC) which keeps the unbound DHPs in solution by the formation of aggregate or micelle-like structures. In contrast LCC are not formed during the ZL process which behave like the DHP reference. The ZT DHP molar masses increase observed is attributed to the reactivity of the high molar mass polymer solubilized by the LCC whereas ZL higher molar mass polymers are precipitated out of the solution and cannot react further.     

Role of dissolution rate and solubility in biodegradation of aromatic compounds.

Strains of Moraxella sp., Pseudomonas sp., and Flavobacterium sp. able to grow on biphenyl were isolated from sewage. The bacteria produced 2.3 to 4.5 g of protein per mol of biphenyl carbon, and similar protein yields were obtained when the isolates were grown on succinate. Mineralization of biphenyl was exponential during the phase of exponential growth of Moraxella sp. and Pseudomonas sp. In biphenyl-supplemented media, Flavobacterium sp. had one exponential phase of growth apparently at the expense of contaminating dissolved carbon in the solution and a second exponential phase during which it mineralized the hydrocarbon. Phase-contrast microscopy did not show significant numbers of cells of these three species on the surface of the solid substrate as it underwent decomposition. Pseudomonas sp. did not form products that affected the solubility of biphenyl, although its excretions did increase the dissolution rate. It was calculated that Pseudomonas sp. consumed 29 nmol of biphenyl per ml in the 1 h after the end of the exponential phase of growth, but 32 nmol of substrate per ml went into solution in that period when the growth rate had declined. In a medium with anthracene as the sole added carbon source, Flavobacterium sp. converted 90% of the substrate to water-soluble products, and a slow mineralization was detected when the cell numbers were not increasing. Flavobacterium sp. and Beijerinckia sp. initially grew exponentially and then arithmetically in media with phenanthrene as the sole carbon source. Calculations based on the growth rates of these bacteria and the rates of dissolution of phenanthrene suggest that the dissolution rate of the hydrocarbon may limit the rate of its biodegradation.     

Aryl 1,4-diazepane compounds as potent and selective CB2 agonists: optimization of drug-like properties and target independent parameters

A high throughput screening campaign identified aryl 1,4-diazepane compounds as potent and selective cannabinoid receptor 2 agonists as compared to cannabinoid receptor 1. This class of compounds suffered from poor drug-like parameters as well as low microsomal stability and poor solubility. Structure-activity relationships are described with a focus on improving the drug-like parameters resulting in compounds with improved solubility and permeability.     

COMPASS II: extended coverage for polymer and drug-like molecule databases

The COMPASS II force field has been developed by extending the coverage of the COMPASS force field (J Phys Chem B 102(38):7338–7364, 1998) to polymer and drug-like molecules found in popular databases. Using a fragmentation method to systematically construct small molecules that exhibit key functional groups found in these databases, parameters applicable to database compounds were efficiently obtained. Based on the same parameterization paradigm as used in the development of the COMPASS force field, new parameters were derived by a combination of fits to quantum mechanical data for valence parameters and experimental liquid and crystal data for nonbond parameters. To preserve the quality of the original COMPASS parameters, a quality assurance suite was used and updated to ensure that additional atom-types and parameters do not interfere with the existing ones. Validation against molecular properties, liquid and crystal densities, and enthalpies, demonstrates that the quality of COMPASS is preserved and the same quality of prediction is achieved for the additional coverage.     

A model for testing compounds influencing porphyrin synthesis

The yeast Saccharomyces cerevisiae cultivated semi-anaerobically in a synthetic medium was used as a model to establish (a) total porphyrin synthesis, (b) ratio of intracellular to extracellular porphyrin concentrations. The antimalarials used for the therapy of porphyria cutanea tarda, chloroquine and pyrimethamine, reduced the total synthesis of porphyrins, pyrimethamine being more effective than chloroquine, like in porphyric patients. Both drugs exerted an antagonistic influence on the release of porphyrins from cells. Chloroquine reduced the concentration ratio of porphyrins while pyrimethamine increased it, apparently through inhibition of permeation of porphyrins. Combined treatment with the two compounds may hold promise for the therapy of porphyria cutanea tarda.