Identification of Natural-Product-Derived Inhibitors of 5-Lipoxygenase Activity by Ligand-Based Virtual Screening

Franke, Lutz; Schwarz, Oliver; Müller‐Kuhrt, Lutz; Hoernig, Christina; Fischer, Lutz; George, Sven; Tanrıkulu, Yusuf; Schneider, Petra; Werz, Oliver; Steinhilber, Dieter; Schneider, Gisbert

doi:10.1021/jm060655w

Cited by 67 publications

(41 citation statements)

References 27 publications

(63 reference statements)

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“…Two new chemotypes (116 and 117 in Fig. 4) strongly inhibited 5-LO in a cellbased and cell-free assay with IC 50 values around 1 and 0.1 mM, respectively [203], demonstrating the potential of such naturalproduct-derived screening libraries for hit and lead structure identification.…”

Section: Alkaloidsmentioning

confidence: 85%

“…For example, by virtual screening of a natural product collection and natural-product-derived combinatorial libraries (430 substances) for potential 5-LO inhibitors grounded on the ªsimilarity principleº, we identified 18 compounds which had mutual pharmacophore features with at least one of 43 known 5-LO inhibitors (that served as query structures) [203]. Two new chemotypes (116 and 117 in Fig.…”

Section: Alkaloidsmentioning

confidence: 99%

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Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

Werz¹

2007

Planta Med

Self Cite

149

134

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The biosynthesis of leukotrienes (LTs) is initiated by the transformation of free arachidonic acid to LTA 4 by 5-lipoxygenase (5-LO). Subsequent enzymatic conversion of LTA 4 yields LTB 4 and the cysteinyl-LTs C 4 , D 4 and E 4 . LTs have prominent functions in pathophysiology and are connected to numerous disorders including bronchial asthma, allergic rhinitis, inflammatory bowel and skin diseases, rheumatoid arthritis, cancer, osteoporosis and cardiovascular diseases. Pharmacological and genetic interruption of the 5-LO pathway or blockade of LT receptors, serving as means for intervention with LTs, may be of therapeutic value for certain related disorders. Natural or plant-derived substances were among the first 5-LO inhibitors identified in the early 1980 s. To date, a huge number of diverse plant-derived compounds have been reported to interfere with 5-LO product synthesis. However, many investigations have addressed the efficacy of a given compound solely in cellular test systems and analysis of direct interference with 5-LO has been neglected. In the first part of this review, the biology and molecular pharmacology of the 5-LO pathway is summarized in order to understand its overall regulation and complexity as well as to comprehend the possible points of attack of compounds that eventually lead to inhibition of 5-LO product formation in intact cells. In the second part, natural compounds that interfere with 5-LO product formation are compiled and grouped into structural classes, and the underlying molecular mechanisms and structureactivity relationships are discussed.

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Section: Alkaloidsmentioning

confidence: 85%

Section: Alkaloidsmentioning

confidence: 99%

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

Werz¹

2007

Planta Med

Self Cite

149

134

View full text Add to dashboard Cite

show abstract

“…For example, ligand-based methods were applied for the drug target enzyme 5-lipoxygenase (5-LO), that catalyzes the first steps in the conversion of arachidonic acid into leukotrienes, which has been associated with atherosclerosis, cancer, and osteoporosis [67]. In the search for new bioactive compounds, 43 known 5-LO inhibitors were assembled and used in similarity searching in the speedCATS software (Fig.…”

Section: Successful Applications Of Lbvsmentioning

confidence: 99%

Virtual Screening and Its Integration with Modern Drug Design Technologies

Güido¹,

Oliva²,

Andricopulo

2008

CMC

162

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Drug discovery is a highly complex and costly process, which demands integrated efforts in several relevant aspects involving innovation, knowledge, information, technologies, expertise, R&D investments and management skills. The shift from traditional to genomics-and proteomics-based drug research has fundamentally transformed key R&D strategies in the pharmaceutical industry addressed to the design of new chemical entities as drug candidates against a variety of biological targets. Therefore, drug discovery has moved toward more rational strategies based on our increasing understanding of the fundamental principles of protein-ligand interactions. The combination of available knowledge of several 3D protein structures with hundreds of thousands of small-molecules have attracted the attention of scientists from all over the world for the application of structure-and ligand-based drug design approaches. In this context, virtual screening technologies have largely enhanced the impact of computational methods applied to chemistry and biology and the goal of applying such methods is to reduce large compound databases and to select a limited number of promising candidates for drug design. This review provides a perspective of the utility of virtual screening in drug design and its integration with other important drug discovery technologies such as high-throughput screening (HTS) and QSAR, highlighting the present challenges, limitations, and future perspectives in medicinal chemistry.

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“…Computer assisted approaches [23], such as docking [24][25][26][27], pharmacophore *Address correspondence to this author at the Drug Discovery Informatics Laboratory, QRC-Qasemi Research Center, Al-Qasemi Academic College, P.O.B. 124, Baqa El-Gharbia 30100, Israel; Tel: + 972-4-6286761/4; Fax: + 972-4-6286762; E-mail: a_rayan@qsm.ac.il modeling [28][29][30] and virtual screening [31][32][33][34] have been carried out and reported related to the field of bioactive natural products. In order to introduce the natural products features into the design of drug candidates, the discriminative features of natural products need to be unraveled.…”

Section: Introductionmentioning

confidence: 99%

Physicochemical Properties of Natural Based Products versus Synthetic Chemicals

Zaid¹,

Raiyn²,

Nasser³

et al. 2010

TONUTRAJ

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Abstract:The majority of the currently used cosmetics and drugs are natural products-based compounds or their derivatives. This could add weight to the argument that natural based products are inherently better tolerated in the body than synthetic chemicals and have higher chance to be approved as new drugs. The present study was undertaken to analyze a natural product database compared to synthetic chemicals and to search for discriminative physicochemical properties that may probably help in differentiating between natural and synthetic compounds. We have formulated rules to assess the natural likeness of chemicals and thereby discriminate between natural-based and synthetic chemicals. A Mathews Correlation Coefficient of 0.5 was obtained; nearly 81% of natural-based products and 68% of synthetic chemicals were precisely classified using this filter. The property criteria for drug-likeness and lead-likeness are more pronounced in natural products rather than synthetic ones. The fraction of synthetic chemicals which are natural-like could have higher chance to be successful drug.

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Identification of Natural-Product-Derived Inhibitors of 5-Lipoxygenase Activity by Ligand-Based Virtual Screening

Cited by 67 publications

References 27 publications

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

Virtual Screening and Its Integration with Modern Drug Design Technologies

Physicochemical Properties of Natural Based Products versus Synthetic Chemicals

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