Computer-aided molecular selection and design of natural bioactive molecules

The search for natural bioactive compounds has led to a renewal of interest in exploring the plant kingdom. Indeed, a more rational search for innovative natural active compounds has become a priority. This review describes the search for new, natural, active compounds by combining the classical ethnopharmacology approach with newer strategies. The proposed computer-aided molecular selection and design (CAMSD) strategy is based on an in-depth exploitation of all the ethnopharmacological, chemical and biological information available. In the first step, the information extracted from various complementary sources - private, literature, Internet - is organized within a database called Phytotech. In the second step, bioinformatic technologies are used to search for new leads based on the molecular and/or the botanical diversity analysis of the Phytotech database. Once a lead is found, the knowledge of involved protein/ligand interaction is improved by molecular modeling. Finally, the activity of the derived bioactive compounds is optimized by pharmacomodulation of the previously selected leads with the help of two- or three-dimensional quantitative structure-activity relationships (2D- or 3D-QSAR) database exploitation. This coherent and global strategy, specially designed for selecting and designing natural bioactive molecules, is based on the hybridization of various chemometric strategies and supported by our own recent examples dealing with acetylcholinesterase inhibition.