title: Strategies for efficient lead structure discovery from natural products.
abstract: This investigation aims to evaluate strategies for an efficient selection of bioactive compounds from the multitude and biodiversity of the plant kingdom. Statistics prove natural products (NPs) as a source leading most consistently to successful development of new drugs. However, there are several reasons why the interest in finding bioactive NPs has generally declined at several major pharmaceutical companies. Their substantial argument is that the research in this field is time-consuming, highly complex and ineffective. A more rational and economic search for new lead structures from nature must therefore be a priority in order to overcome these problems. In this paper, different strategies are described to exploit the molecular diversity of bioactive secondary metabolites, namely classical pharmacognostic approaches and computational methods. The latter include various data mining tools, like virtual screening filtering experiments using pharmacophore models, docking studies, and neural networks, which help to establish a relationship between chemical structure and biological activity. The strengths and weaknesses of these methods will be shown in this review. Focusing on selected targets within the arachidonic acid cascade (phospholipase A(2), 5-lipoxygenase, cyclooxygenase-1 and -2), several studies of successful discoveries in the field of anti-inflammatory NPs were scrutinized for the applied strategies. Both the compilation of relevant published data and recent studies supported by our own research clearly demonstrate the benefits of the synergistic effect of a hybridization of these strategies for an effective drug discovery from natural ingredients.
authors.affiliation: Institute of Pharmacy/Pharmacognosy, Josef-Moeller-Haus, Innrain 52c, Leopold-Franzens-University Innsbruck, 6020 Innsbruck, Austria. judith.rollinger@uibk.ac.at
authors.forename: J M
authors.initials: JM
authors.lastname: Rollinger
authors.forename: T
authors.initials: T
authors.lastname: Langer
authors.forename: H
authors.initials: H
authors.lastname: Stuppner
mesh_terms: D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D004345:Drug Industry / Q000379:methods* / Q000639:trends; D029001:Herbal Medicine; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D016571:Neural Networks, Computer; D010936:Plant Extracts / Q000737:chemistry; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D008024:Ligands; D010936:Plant Extracts; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases