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ABSTRACT: Activity data for small molecules are invaluable in chemoinformatics. Various bioactivity databases exist containing detailed information of target proteins and quantitative binding data for small molecules extracted from journals and patents. In the current work, we have merged several public and commercial bioactivity databases into one bioactivity metabase. The molecular presentation, target information, and activity data of the vendor databases were standardized. The main motivation of the work was to create a single relational database which allows fast and simple data retrieval by in-house scientists. Second, we wanted to know the amount of overlap between databases by commercial and public vendors to see whether the former contain data complementing the latter. Third, we quantified the degree of inconsistency between data sources by comparing data points derived from the same scientific article cited by more than one vendor. We found that each data source contains unique data which is due to different scientific articles cited by the vendors. When comparing data derived from the same article we found that inconsistencies between the vendors are common. In conclusion, using databases of different vendors is still useful since the data overlap is not complete. It should be noted that this can be partially explained by the inconsistencies and errors in the source data.
Journal of Chemical Information and Modeling 12/2011; 52(2):319-26. · 4.68 Impact Factor
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ABSTRACT: Most drugs act on a multitude of targets rather than on one single target. Polypharmacology, an upcoming branch of pharmaceutical science, deals with the recognition of these off-target activities of small chemical compounds. Due to the high amount of data to be processed, application of computational methods is indispensable in this area. This review summarizes the most important in silico approaches for polypharmacology. The described methods comprise network pharmacology, machine learning techniques and chemogenomic approaches. The use of these methods for drug repurposing as a branch of drug discovery and development is discussed. Furthermore, a broad range of prospective applications is summarized to give the reader an overview of possibilities and limitations of the described techniques.
Future medicinal chemistry 06/2011; 3(8):961-8. · 2.52 Impact Factor
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Christian Feisst,
Carlo Pergola,
Marija Rakonjac,
Antonietta Rossi,
Andreas Koeberle,
Gabriele Dodt,
Marika Hoffmann,
Christina Hoernig,
Lutz Fischer,
Dieter Steinhilber, Lutz Franke,
Gisbert Schneider,
Olof Rådmark,
Lidia Sautebin,
Oliver Werz
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ABSTRACT: We previously showed that, in vitro, hyperforin from St. John's wort (Hypericum perforatum) inhibits 5-lipoxygenase (5-LO), the key enzyme in leukotriene biosynthesis. Here, we demonstrate that hyperforin possesses a novel and unique molecular pharmacological profile as a 5-LO inhibitor with remarkable efficacy in vivo. Hyperforin (4 mg/kg, i.p.) significantly suppressed leukotriene B(4) formation in pleural exudates of carrageenan-treated rats associated with potent anti-inflammatory effectiveness. Inhibition of 5-LO by hyperforin, but not by the iron-ligand type 5-LO inhibitor BWA4C or the nonredox-type inhibitor ZM230487, was abolished in the presence of phosphatidylcholine and strongly reduced by mutation (W13A-W75A-W102A) of the 5-LO C2-like domain. Moreover, hyperforin impaired the interaction of 5-LO with coactosin-like protein and abrogated 5-LO nuclear membrane translocation in ionomycin-stimulated neutrophils, processes that are typically mediated via the regulatory 5-LO C2-like domain. Together, hyperforin is a novel type of 5-LO inhibitor apparently acting by interference with the C2-like domain, with high effectiveness in vivo.
Cellular and Molecular Life Sciences CMLS 09/2009; 66(16):2759-71. · 6.57 Impact Factor
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Lars Tausch,
Arne Henkel,
Ulf Siemoneit,
Daniel Poeckel,
Nicole Kather, Lutz Franke,
Bettina Hofmann,
Gisbert Schneider,
Carlo Angioni,
Gerd Geisslinger,
Carsten Skarke,
Wolfgang Holtmeier,
Tobias Beckhaus,
Michael Karas,
Johann Jauch,
Oliver Werz
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ABSTRACT: Frankincense preparations, used in folk medicine to cure inflammatory diseases, showed anti-inflammatory effectiveness in animal models and clinical trials. Boswellic acids (BAs) constitute major pharmacological principles of frankincense, but their targets and the underlying molecular modes of action are still unclear. Using a BA-affinity Sepharose matrix, a 26-kDa protein was selectively precipitated from human neutrophils and identified as the lysosomal protease cathepsin G (catG) by mass spectrometry (MALDI-TOF) and by immunological analysis. In rigid automated molecular docking experiments BAs tightly bound to the active center of catG, occupying the same part of the binding site as the synthetic catG inhibitor JNJ-10311795 (2-[3-[methyl[1-(2-naphthoyl)piperidin-4-yl]amino]carbonyl)-2-naphthyl]-1-(1-naphthyl)-2-oxoethylphosphonic acid). BAs potently suppressed the proteolytic activity of catG (IC(50) of approximately 600 nM) in a competitive and reversible manner. Related serine proteases were significantly less sensitive against BAs (leukocyte elastase, chymotrypsin, proteinase-3) or not affected (tryptase, chymase). BAs inhibited chemoinvasion but not chemotaxis of challenged neutrophils, and they suppressed Ca(2+) mobilization in human platelets induced by isolated catG or by catG released from activated neutrophils. Finally, oral administration of defined frankincense extracts significantly reduced catG activities in human blood ex vivo vs placebo. In conclusion, we show that catG is a functional and pharmacologically relevant target of BAs, and interference with catG could explain some of the anti-inflammatory properties of frankincense.
The Journal of Immunology 08/2009; 183(5):3433-42. · 5.79 Impact Factor
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ChemMedChem 09/2008; 3(10):1535-8. · 3.15 Impact Factor
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ABSTRACT: Boswellic acids (BAs) are assumed as the anti-inflammatory principles of Boswellia species. Initially, it was found that BAs inhibit leukotriene biosynthesis and 5-lipoxygenase (EC number 1.13.11.34), whereas suppression of prostaglandin formation and inhibition of cyclooxygenases (COX, EC number 1.14.99.1) has been excluded. Recently, we demonstrated that BAs also interfere with platelet-type 12-lipoxygenase. Here, we show that BAs, preferably 3-O-acetyl-11-keto-beta-BA (AKBA), concentration-dependently inhibit COX-1 product formation in intact human platelets (IC(50)=6 microM) as well as the activity of isolated COX-1 enzyme in cell-free assays (IC(50)=32 microM). The inhibitory effect of AKBA is reversible, and increased levels of arachidonic acid (AA) as substrate for COX-1 impair the efficacy. COX-1 in platelet lysates or isolated COX-1 selectively bound to an affinity matrix composed of immobilized BAs linked via glutaric acid to sepharose and this binding was reversed by ibuprofen or AA. Automated molecular docking of BAs into X-ray structures of COX-1 yielded positive Chemscore values for BAs, indicating favorable binding to the active site of the enzyme. In contrast, COX-2 was less efficiently inhibited by BAs as compared to COX-1, and pull-down experiments as well as docking studies exclude strong affinities of BAs towards COX-2. In conclusion, BAs, in particular AKBA, directly interfere with COX-1 and may mediate their anti-inflammatory actions not only by suppression of lipoxygenases, but also by inhibiting cyclooxygenases, preferentially COX-1.
Biochemical Pharmacology 02/2008; 75(2):503-13. · 4.70 Impact Factor
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Lutz Franke,
Oliver Schwarz,
Lutz Müller-Kuhrt,
Christina Hoernig,
Lutz Fischer,
Sven George,
Yusuf Tanrikulu,
Petra Schneider,
Oliver Werz,
Dieter Steinhilber,
Gisbert Schneider
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ABSTRACT: A natural product collection and natural-product-derived combinatorial libraries were virtually screened for potential inhibitors of human 5-lipoxygenase (5-LO) activity. We followed a sequential ligand-based approach in two steps. First, similarity searching with a topological pharmacophore descriptor (CATS 2D method) was performed to enable scaffold-hopping. Eighteen compounds were selected from a virtual hit list of 430 substances, which had mutual pharmacophore features with at least one of 43 known 5-LO inhibitors that served as query structures. Two new chemotypes exhibited significant activity in a cell-based 5-LO activity assay. The two most potent molecules served as seed structures for a second virtual screening round. This time, a focused natural-product-derived combinatorial library was analyzed by different ligand-based virtual screening methods. The best molecules from the final set of screening candidates potently suppressed 5-LO activity in intact cells and may represent a novel class of 5-LO inhibitors. The results demonstrate the potential of natural-product-derived screening libraries for hit and lead structure identification.
Journal of Medicinal Chemistry 06/2007; 50(11):2640-6. · 5.25 Impact Factor
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ABSTRACT: A virtual screening method is presented that is grounded on a receptor-derived pharmacophore model termed "virtual ligand" or "pseudo-ligand". The model represents an idealized constellation of potential ligand sites that interact with residues of the binding pocket. For rapid virtual screening of compound libraries the potential pharmacophore points of the virtual ligand are encoded as an alignment-free correlation vector, avoiding spatial alignment of pharmacophore features between the pharmacophore query (i.e., the virtual ligand) and the candidate molecule. The method was successfully applied to retrieving factor Xa inhibitors from a Ugi three-component combinatorial library, and yielded high enrichment of actives in a retrospective search for cyclooxygenase-2 (COX-2) inhibitors. The approach provides a concept for "de-orphanizing" potential drug targets and identifying ligands for hitherto unexplored or allosteric binding pockets.
Combinatorial Chemistry & High Throughput Screening 07/2006; 9(5):359-64. · 1.78 Impact Factor
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ABSTRACT: Support vector machines (SVM) were trained to predict cyclooxygenase 2 (COX-2) and thrombin inhibitors. The classifiers were obtained using sets of known COX-2 and thrombin inhibitors as "positive examples" and a large collection of screening compounds as "negative examples". Molecules were encoded by topological pharmacophore-point triangles. In retrospective virtual screening, 50-90% of the known active compounds were listed within the first 0.1% of the ranked database. To check the validity of the constructed classifiers, we developed a method for feature extraction and visualization using SVM. As a result, potential pharmacophore points were weighted according to their importance for COX-2 and thrombin inhibition. Known thrombin and COX-2 pharmacophore points were correctly recognized by the machine learning system. In a prospective virtual screening study, several potential COX-2 inhibitors were predicted and tested in a cellular activity assay. A benzimidazole derivative exhibited significant inhibitory activity with an IC(50) of 0.2 microM, which is better than Celecoxib in our assay. It was demonstrated that the SVM machine-learning method can be used in virtual screening and be analyzed in a human-interpretable way that results in a set of rules for designing novel molecules.
Journal of Medicinal Chemistry 12/2005; 48(22):6997-7004. · 5.25 Impact Factor
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ABSTRACT: Myrtucommulone (MC) and semimyrtucommulone (S-MC) are unique oligomeric, nonprenylated acylphloroglucinols contained in the leaves of myrtle (Myrtus communis). Although extracts of myrtle have been traditionally used in folk medicine for the treatment of various disorders, studies addressing select cellular or molecular pharmacological properties of these extracts or specific ingredients thereof are rare. Here, we show for the first time that MC and S-MC potently suppress the biosynthesis of eicosanoids by direct inhibiting cyclooxygenase-1 and 5-lipoxygenase in vitro and in vivo at IC50 values in the range of 1.8 to 29 microM. Moreover, we show that MC and S-MC prevent the mobilization of Ca2+ in polymorphonuclear leukocytes, mediated by G protein signaling pathways at IC50 values of 0.55 and 4.5 microM, respectively, and suppress the formation of reactive oxygen species and the release of elastase at comparable concentrations. The isobutyrophenone core of MC as well as S-MC was much less potent or even not active at all. In addition, MC or S-MC only partially inhibited peroxide formation or failed to block Ca2+ mobilization and elastase release when polymorphonuclear leukocytes were challenged with ionomycin that circumvents G protein signaling for cell activation. We conclude that, in view of their ability to suppress typical proinflammatory cellular responses, the unique acylphloroglucinols MC and S-MC from myrtle may possess an anti-inflammatory potential, suggesting their therapeutic use for the treatment of diseases related to inflammation and allergy.
Journal of Pharmacology and Experimental Therapeutics 11/2005; 315(1):389-96. · 3.83 Impact Factor
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ABSTRACT: 5-Lipoxygenase (5-LO) is a tightly regulated enzyme in the synthesis of bioactive lipids from arachidonic acid. Here, we demonstrate that 5-LO is regulated by caspases, which are signaling molecules that control critical biological processes by means of specific limited proteolysis. Cell splitting of the Epstein-Barr virus-transformed B lymphocytic cell line BL41-E95-A caused a pronounced, but transient, reduction of functional 5-LO protein, accompanied by the appearance of a 62-kDa 5-LO cleavage product. In parallel, splitting of BL41-E95-A cells induced activation of caspase-6 (casp-6) and casp-8. Caspase activation and 5-LO degradation were blocked by the protein-synthesis inhibitor cycloheximide, and cell-permeable peptide inhibitors of casp-6 and casp-8 prevented 5-LO cleavage. Activation of casp-6 and casp-8 was connected to subsequent enhancement of cell proliferation, whereas selective caspase inhibition blocked cell growth. Last, isolated human 5-LO was cleaved by recombinant casp-6 in vitro to a 58-kDa fragment. Based on site-directed mutagenesis studies, 5-LO is cleaved by casp-6 after Asp-170, which in a homology-based 3D model of 5-LO is located on the enzyme periphery. We suggest that splitting of BL41-E95-A cells induces de novo synthesis of a protein involved in the activation of casp-6, which cleaves 5-LO.
Proceedings of the National Academy of Sciences 10/2005; 102(37):13164-9. · 9.68 Impact Factor
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ABSTRACT: Correlation vector methods were tested for their usefulness in ligand-based virtual screening. Three molecular descriptors--two based on potential pharmacophore points and one on partial atom charges--and three similarity measures--the Manhattan distance, the Euclidian distance and the Tanimoto coefficient--were compared. The alignment-free descriptors seem to be particularly applicable when a course-grain filtering of data sets is required in combination with a high execution speed. Significant enrichment of actives was obtained by retrospective analysis. The cumulative percentages for all three descriptors allow for the retrieval of up to 78% of the active molecules in the first five percent of the reference database. Different descriptors retrieved only weakly overlapping sets of active molecules among the top-ranking compounds. If a single similarity index is to be used, the Manhattan distance seems to be particularly applicable. Generally, none of the three different descriptors tested in this study clearly outperformed the others. The suitability of a descriptor critically depends on the ligand-receptor interaction under investigation. For ligand-based similarity searching it is recommended to exploit several descriptors in parallel.
Journal of Computer-Aided Molecular Design 11/2003; 17(10):687-98. · 3.39 Impact Factor
