MONA - Interactive manipulation of molecule collections.

: Working with small-molecule datasets is a routine task for cheminformaticians and chemists. The analysis and comparison of vendor catalogues and the compilation of promising candidates as starting points for screening campaigns are but a few very common applications. The workflows applied for this purpose usually consist of multiple basic cheminformatics tasks such as checking for duplicates or filtering by physico-chemical properties. Pipelining tools allow to create and change such workflows without much effort, but usually do not support interventions once the pipeline has been started. In many contexts, however, the best suited workflow is not known in advance, thus making it necessary to take the results of the previous steps into consideration before proceeding.To support intuition-driven processing of compound collections, we developed MONA, an interactive tool that has been designed to prepare and visualize large small-molecule datasets. Using an SQL database common cheminformatics tasks such as analysis and filtering can be performed interactively with various methods for visual support. Great care was taken in creating a simple, intuitive user interface which can be instantly used without any setup steps. MONA combines the interactivity of molecule database systems with the simplicity of pipelining tools, thus enabling the case-to-case application of chemistry expert knowledge. The current version is available free of charge for academic use and can be downloaded at http://www.zbh.uni-hamburg.de/mona.

Reading PDB: perception of molecules from 3D atomic coordinates.

The analysis of small molecule crystal structures is a common way to gather valuable information for drug development. The necessary structural data is usually provided in specific file formats containing only element identities and three-dimensional atomic coordinates as reliable chemical information. Consequently, the automated perception of molecular structures from atomic coordinates has become a standard task in cheminformatics. The molecules generated by such methods must be both chemically valid and reasonable to provide a reliable basis for subsequent calculations. This can be a difficult task since the provided coordinates may deviate from ideal molecular geometries due to experimental uncertainties or low resolution. Additionally, the quality of the input data often differs significantly thus making it difficult to distinguish between actual structural features and mere geometric distortions. We present a method for the generation of molecular structures from atomic coordinates based on the recently published NAOMI model. By making use of this consistent chemical description, our method is able to generate reliable results even with input data of low quality. Molecules from 363 Protein Data Bank (PDB) entries could be perceived with a success rate of 98%, a result which could not be achieved with previously described methods. The robustness of our approach has been assessed by processing all small molecules from the PDB and comparing them to reference structures. The complete data set can be processed in less than 3 min, thus showing that our approach is suitable for large scale applications.

NAOMI: on the almost trivial task of reading molecules from different file formats.

In most cheminformatics workflows, chemical information is stored in files which provide the necessary data for subsequent calculations. The correct interpretation of the file formats is an important prerequisite to obtain meaningful results. Consistent reading of molecules from files, however, is not an easy task. Each file format implicitly represents an underlying chemical model, which has to be taken into consideration when the input data is processed. Additionally, many data sources contain invalid molecules. These have to be identified and either corrected or discarded. We present the chemical file format converter NAOMI, which provides efficient procedures for reliable handling of molecules from the common chemical file formats SDF, MOL2, and SMILES. These procedures are based on a consistent chemical model which has been designed for the appropriate representation of molecules relevant in the context of drug discovery. NAOMI's functionality is tested by round robin file IO exercises with public data sets, which we believe should become a standard test for every cheminformatics tool.

Evaluation of seasonal variations of the structure and anti-inflammatory activity of sulfated polysaccharides extracted from the red alga Delesseria sanguinea (Hudson) Lamouroux (Ceramiales, Delesseriaceae).

Delesseria sanguinea (Hudson) Lamouroux was shown to contain sulfated polysaccharides (D.s.-SP) with anti-inflammatory effects. This red macroalga turned out to dominantly populate an artificial reef in the southwestern Baltic Sea. An important aspect for its economical utilization is to obtain D.s.-SP in a reproducible quality. The aim of the study was to evaluate the seasonal variability of D.s.-SP; for this, algae batches were harvested monthly over the period of one year. Structural and pharmacological characterization of the isolated D.s.-SP showed that an optimized and standardized aqueous extraction (85 degrees C) leads to reproducible products without any significant seasonal variations of their elastase and hyaluronidase inhibitory activities. Besides the yields (from 17.9% in April to 6.12% in September), only the glucose content of the D.s.-SP batches seasonally varied (April, 7.48% +/- 1.00%, September, 22.8% +/- 1.2%) due to certain coextraction of starch-like glucans. In principle, algae material can be harvested throughout the year, but the optimum harvesting time is in spring.

Pharmacological profiles of animal- and nonanimal-derived sulfated polysaccharides--comparison of unfractionated heparin, the semisynthetic glucan sulfate PS3, and the sulfated polysaccharide fraction isolated from Delesseria sanguinea.

Sulfated polysaccharides (SP) such as heparin are known to exhibit a wide range of biological activities, e.g., anticoagulant, anti-inflammatory, and antimetastastic effects. However, since the anticoagulant activity of heparin is dominating, its therapeutic use for other medical indications is limited due to an associated risk of bleeding. Further disadvantages of heparin are its animal origin, the shortage of resources, and its complex and variable composition. However, SP without these limitations may represent a substance class with good prospects for applications other than anticoagulation. In this study, the in vitro pharmacological profiles of two nonanimal-derived SP were investigated in comparison with unfractionated heparin. One is the natural SP fraction from the red algae Delesseria sanguinea (D.s.-SP). The other one is the chemically defined PS3, a semisynthetic beta-1,3-glucan sulfate with proven in vivo anti-inflammatory and antimetastatic activities. All three polysaccharides were examined in vitro for their inhibitory effects on the coagulation and complement system, polymorphonuclear neutrophil elastase, hyaluronidase, matrix metalloproteinase-1, heparanase, and p-selectin-mediated cell adhesion. Compared with heparin, the nonanimal-derived polysaccharides have a four times weaker anticoagulant activity, but mostly exhibit stronger (1.4-224 times) effects on test systems investigating targets of inflammation or metastasis. According to their different structures, PS3 and D.s.-SP differ in their pharmacological profile with PS3 being the strongest inhibitor of heparanase and cell adhesion and D.s.-SP being the strongest inhibitor of hyaluronidase and complement activation. Considering both pharmacological profile and pharmaceutical quality parameters, PS3 represents a candidate for further development as an anti-inflammatory or antimetastatic drug whereas D.s.-SP might have perspectives for cosmetic applications.

Elastase inhibition assay with peptide substrates - an example for the limited comparability of in vitro results.

Many factors such as buffer, pH, or enzyme concentration influence the inhibitory activity of test compounds in IN VITRO enzyme inhibition assays. The purpose of this study was to evaluate whether the variation of the synthetic substrate has an influence on the IC (50) values as well. As an exemplary enzyme, we have chosen polymorphonuclear neutrophil elastase (PMNE), which is considered as a promising target in the therapy for inflammatory and tumour diseases. A well established, validated IN VITRO PMNE inhibition assay was performed with three different synthetic peptide substrates (S-2484, L-1335, I-1270). As inhibitors ursolic acid, unfractionated heparin (UFH), the semisynthetic glucan sulfate PS3, and sulfated polysaccharides from the red algae DELESSERIA SANGUINEA (D.s.-SP), were used. The maximum achievable PMNE inhibition by the test compounds was shown to be determined by the substrate: 60 to 70 % (L-1335 and S-2484) or 90 % (I-1270). Furthermore, the IC (50) values of the inhibitors turned out to strongly vary in dependence on the substrate, although the used peptide substrates are structurally very similar. The derived activities differed by up to 480 %. In addition, the potencies of the test compounds in relation to each other altered considerably. In conclusion, by the choice of the enzyme substrate, both the apparent maximum activity and the IC (50) of an inhibitor can be influenced. Therefore, only results from identical test systems should be compared..