Resolution of controversies in drug/receptor interactions by protein structure. Limitations and pharmacological solutions

Structural biology offers breakthroughs for key issues in receptors, ion channels and transporters. Unfortunately, while knowledge is growing exponentially about receptors and drug targets, there is also an exponential knowledge of all the variables involved. A key issue for structure-based drug design is if there are distinct outcomes from a single structurally defined site. The ways in which drugs can interact with G-protein-coupled receptors (GPCRs) at the orthosteric site can be multiple, and ligands can also interact with allosteric sites. Receptors may exist as homo- or heterodimers, with the potential for distinct pharmacology, and NC-IUPHAR has proposed stringent criteria for recognition of heterodimers (Pin et al., 2007). Furthermore, some drugs have the capacity for activating different signalling cascades from a single receptor (Urban et al., 2007) indicating unique pharmacology. Thus although specific drugs were the main tool by which receptors were (and still can be, if appropriate precautions are taken) classified, drugs may also have distinct pharmacology at certain receptors depending on their chemical structure, showing drug-specific pharmacology rather than the specific-drug pharmacology which had been used in the past to define (and limit) drug classes. Primary structure is an essential but occasionally treacherous tool for defining receptors because distinct primary structures may evolve to perform similar function. This has immense implications in drug screening, and development - which also entails much testing, and selection, in pathophysiological situations.