ChemGPS-NP: Tuned for navigation in biologically relevant chemical space
ABSTRACT Natural compounds are evolutionary selected and prevalidated by Nature, displaying a unique chemical diversity and a corresponding diversity of biological activities. These features make them highly interesting for studies of chemical biology, and in the pharmaceutical industry for development of new leads. Of utmost importance, for the discovery of new biologically active compounds, is the identification and charting of the corresponding biologically relevant chemical space. The primary key to this is the coverage of the natural products' chemical space. Here we introduce ChemGPS-NP, a new tool tuned for handling the chemical diversity encountered in natural products research, in contrast to previous tools focused on the much more restricted drug-like chemical space. The aim is to provide a framework for making compound classification and comparison more efficient and stringent, to identify volumes of chemical space related to particular biological activities, and to track changes in chemical properties due to, for example, evolutionary traits and modifications in biosynthesis. Physical-chemical properties not directly discernible from structural data can be discovered, making selection more efficient and increasing the probability of hit generation when screening natural compounds and analogues.
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ABSTRACT: Identifying bioactive molecules from complex biomasses requires careful selection and execution of relevant bioassays in the various stages of the discovery process of potential leads and targets. The aim of this review is to share our long-term experience in bioassay-guided isolation, and mechanistic studies, of bioactive compounds from different organisms in nature with emphasis on anti-inflammatory and antimicrobial activity. In the search for anti-inflammatory activity, in vivo and in vitro model combinations with enzymes and cells involved in the inflammatory process have been used, such as cyclooxygenases, human neutrophils and human cancer cell lines. Methods concerning adsorption and perforation of bacteria, fungi, human cells and model membranes, have been developed and optimised, with emphasis on antimicrobial peptides and their interaction with the membrane target, in particular their ability to distinguish host from pathogen. A long-term research has provided experience of selection and combination of bioassay models, which has led to an increased understanding of ethnopharmacological and ecological observations, together with in-depth knowledge of mode of action of isolated compounds. A more multidisciplinary approach and a higher degree of fundamental research in development of bioassays are often necessary to identify and to fully understand the mode of action of bioactive molecules with novel structure-activity relationships from natural sources. Copyright © 2013 John Wiley & Sons, Ltd.Phytochemical Analysis 01/2014; 25(1). DOI:10.1002/pca.2468 · 2.45 Impact Factor
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ABSTRACT: Drug discovery based on natural products has a long successful history. To further advance the identification of new drugs from compounds of natural origin, natural product research is increasingly being combined with computer-aided drug design techniques. Herein, we review the recent advances in the application of chemoin-formatics methods to quantify the chemical diversity and structural complexity of natural products and analyze their distribution in chemical space. We also discuss the progress in virtual screening to systematically identify bioactive compounds in natural products databases and the advancement of target fishing methods to uncover molecular targets of compounds from natural origin. www.relaquim.com
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ABSTRACT: In this contribution, a chemical collection of aromatic compounds was screened for inhibition on butyrylcholinesterase (BChE)'s hydrolase activity using Ellman's reaction. A set of diarylimidazoles was identified as highly selective inhibitors of BChE hydrolase activity and amyloid β (Aβ) fibril formation. New derivatives were synthesized resulting in several additional hits, from which the most active was 6c, 4-(3-ethylthiophenyl)-2-(3-thienyl)-1H-imidazole, an uncompetitive inhibitor of BChE hydrolase activity (IC₅₀ BChE=0.10 μM; K(i)=0.073 ± 0.011 μM) acting also on Aβ fibril formation (IC₅₀=5.8 μM). With the aid of structure-activity relationship (SAR) studies, chemical motifs influencing the BChE inhibitory activity of these imidazoles were proposed. These bifunctional inhibitors represent good tools in basic studies of BChE and/or promising lead molecules for AD therapy.European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 11/2011; 45(1-2):169-83. DOI:10.1016/j.ejps.2011.11.004 · 3.01 Impact Factor