Molecular modelling of drug targets: the past, the present and the future

Most currently used therapeutic drugs have an enzyme or a membrane-bound receptor as site of action. The sequencing of the human and other genomes has provided a potential to identify many hitherto unknown proteins that might serve as new drug targets. To achieve this, knowledge about three-dimensional protein structures is crucial for the understanding of their functional mechanisms, and for a rational drug design. Over the last decade atomic resolution crystal structures of soluble proteins have been reported in a rapidly increasing number, but the detailed three-dimensional structures are still unknown for the majority of membrane proteins since their membrane association makes experimental structure determinations complicated. Computerized modelling of protein structures, based on experimentally determined structures of homologue proteins, may be a useful methodological alternative, especially for membrane proteins. In the past, molecular modelling of transporters and G-protein-coupled receptors was based on low-resolution structural data obtained by cryo-electron microscopy. Recent high-resolution crystal structure determinations of a G-protein-coupled receptor, rhodopsin, and several different transporter proteins and ion channels have enabled construction of more accurate receptor and transporter models. For the future, collaborative structural genomics initiatives aim at determining the three-dimensional structure of all known proteins, based on a combination of experimental structure determination and molecular modelling. Development of still more powerful computer hardware and software will enable extensive studies of the protein structure and dynamics of new potential drug targets, but raises a new challenge in the validation and calibration of computerized methods of biosimulations.