Bioinformatics: from genome to drug targets

The complete sequence determination of the human genome marks the start of a new era in biological science, with focus shifting from sequencing to functional mechanisms of gene products. In addition to effects on gene expression, most of the currently used therapeutic drugs either have enzymes or membrane proteins as their molecular targets of action. These membrane proteins include ion channels and transporters of small molecules, and receptors that convey signals from one side of a membrane to the other. Membrane proteins are thus involved in a variety of cellular processes and have a large potential as targets for new drug discovery. However, detailed structural information is still lacking for the majority of membrane proteins since their association with membrane constituents make NMR (nuclear magnetic resonance) spectroscopic and X-ray diffraction determinations difficult. Molecular modelling by biocomputing is a methodological alternative for structural studies of membrane proteins, but has to be based on experimental structural information in addition to computational techniques. A combination of bioinformatics and experimental techniques was used to model membrane proteins from two different classes, secondary transporters of the sodium:neurotransmitter symporter family (SNF transporters), and G-protein coupled receptors (GPCRs). The protein models were used to examine ligand-protein interactions and signalling/transport mechanisms, and to design experimental site-directed mutagenesis studies. Such studies have provided new insight into the detailed molecular mechanisms of two important classes of membrane proteins, which may be of value in the discovery and development of new pharmaceuticals.