Quantitative structure-activity relationships (QSAR) and molecular modelling in cancer research

Abstract

The methods of quantitative structure-activity relationships and molecular modelling that have developed during the last 25 years are nowadays widely applied to describe the relationships between chemical structures of molecules and their biological activities in a quantitative manner. In cancer research also, many attempts have been made to understand structure-activity relationships and to design new antitumor drugs on a more rational basis. Owing to the enormous number of publications, only a few, typical examples are reviewed in this editorial. Much emphasis is given to a discussion of the limitations and the inherent problems of all the different approaches. As a result of the progress in our knowledge derived from experimental methods, the computational methods improve in their predictive ability, thus leading to more reliable results. However, the quantitative description of structure-activity relationships, as well as the modelling of drug-receptor interactions, are still (and will remain for the near future) very difficult. The transport and the distribution of a drug in a biological system is a function of its lipophilicity and its degree of dissociation or ionization at the pH value of the aqueous phases of the system. The interaction of the drug with its binding site at the receptor is determined by the lipophilicity pattern, the charge distribution, the electron density, and the polarizability pattern at the surface of the molecule. Of course, the three-dimensional structure of the molecule is of utmost importance for its fit to the binding site; however, in the case of a more or less flexible molecule, the bound conformation need not be identical to the minimum energy conformation; a less favored conformation may bind to the receptor, when the net interaction energy is large enough to compensate for the energy differences, provided the energy barriers between these conformations are not too large. Not only the ligand, but also the binding site can change its conformation, thus, a flexible fit between both partners occurs. Additional complications arise from different binding modes of chemically closely related molecules, from the insertion of water molecules at the binding site, and from entropy effects. Nature, as well as science, is not trivial. How can we then expect simple answers to complex questions?