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.

The pharmaceutical industry and natural products: historical status and new trends

“…Reverse pharmacology also known as ''target based drug discovery'' became popular after the sequencing of the human genome which allowed for the rapid cloning and synthesis of large quantities of purified proteins. In this context ''Bedside to Bench'' approaches in combinations with systems biology may also be of great interest and the application of a combination of ethno-pharmacological know-how with modern in silico tools may lead to the discovery of new NPs (Rollinger et al 2006;Rollinger 2011). Gene differential expression technologies in mechanistic studies of NP-derived drugs have also shown to be of significant potential (Chen and Jiang 2012).…”

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

“…Nowadays, the efficient discovery of new lead structures as 5-LO inhibitors from the plant kingdom applies different strategies including ligand-based virtual filtering experiments using pharmacophore models, docking studies and neural networks [202]. 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].…”

Antibacterial activity of some African medicinal plants used traditionally against infectious diseases

“…The large number of natural product-derived antibiotics may be due, in part, to the evolution of secondary metabolites as a defense strategy against the environmental stresses. This feature, coupled with their huge structural diversity and great biodiversity, makes natural products an outstanding and challenging subject to drug discovery and development (Rollinger et al, 2006). It is estimated that infectious diseases are directly responsible for 26% of annual deaths worldwide (Morens et al, 2008).…”