Identification of bio-active natural products by virtual scr

Motivation: New high-throughput strategies developed and introduced into the drug discovery process at the end of the 20th century proved to be highly efficient. However, the disappointing number of new drugs launched since then shows that these strategies alone are not enough effective. Thus, novel concepts in the drug discovery process are needed. Inflammation is part of numerous pathological conditions, including atherosclerosis, the metabolic syndrome, sepsis and cancer; all of them lacking satisfying treatment and/or effective concepts of prevention. Natural products (NPs) have always been an important source of new drug leads. About 60 % of the new drugs approved in the last 20 years are derived from or based on NPs. The aim of this national consortium is the identification and characterisation (chemical and biological/pharmacological) of compounds capable to combat inflammatory processes specifically in the cardiovascular system. Strategy: This aim will be approached by a unique combination of strategies including the following aspects: (i) As pool for the discovery of anti-inflammatory agents we will use NPs, which still are important and effective sources for new drugs or leads. (ii) We will apply in silico tools like pharmacophore modelling and virtual screening filtering experiments in order to identify compounds promising for pharmacological evaluation (` molecular/computational approach); (iii) We intend to explore the traditional knowledge about plants to select promising candidates for phytochemical and subsequent pharmacological investigation (`ethnopharmacology/bioguided approach). Candidates of both approaches will be subjected to mechanistic studies as well as preclinical profiling. To address the potential problems of identification and reproducibility of material supply conservation issues will be addressed and molecular biological and biotechnological approaches will be employed. To follow this concept an interdisciplinary consortium connecting five different universities from Innsbruck, Graz and Vienna was installed representing groups working in the fields of ethnopharmacology, pharmacophore modelling/virtual screening, applied botany, chemistry, pharmacology, vascular biology and plant biotechnology. Expected outcome: The combined use of computational techniques including NP databases with traditional knowledge, high-tech chemical analysis and a broad range of in vitro, cell-based and in vivo pharmacological models is expected to deliver promising candidates capable to combat inflammatory processes specifically in the cardiovascular system. Mechanistic studies are expected to contribute to a better understanding of molecular processes in inflammation.