Virtual experiments — A modern alchemy?

In the absence of an experimental receptor structure, biomedical research often relies on QSAR techniques for estimating binding energies of potential drug candidates. While 3D-QSAR is widely used in the drug design community, such concepts would seem to be limited by two approximations: the use of an averaged receptor model to represent the flexible bioregulator and the pharmacophore hypothesis. A 4D-QSAR concept developed at our laboratory not only takes local induced fit into account but also allows for the representation of the ligand molecules by an ensemble of conformation, orientations, and protonation states. Toxic agents, particularly those that exert their actions with a great deal of specificity, sometimes act via receptors to which they bind with high affinity. Our laboratory is currently establishing a virtual laboratory on the Internet to predict harmful effects triggered by drugs or chemicals and their metabolites in silico. This database shall be continuously extended to include surrogates for any bioregulator known or presumed to mediate toxicity or being associated with other harmful effects. Free access to this virtual laboratory shall allow any interested party (academic, industrial, government) to quickly estimate the harmful potential of any given substance prior to its synthesis. This is achieved by generating the three-dimensional structure of a given compound and all it