Transition state analysis to guide drug discovery.

There is an urgent need to find better methods to discover drugs. A third of clinical drugs target G-protein-coupled receptors (GPCRs). When a GPCR is activated by a drug, it changes its structural shape (conformation). Activation proceeds via a series of structural intermediates. The pathway of intermediate conformations dictates the intracellular signalling pathway activated by the drug:receptor complex. Currently it is not possible to predict if a drug will signal (efficacy) and by which pathway (signalling bias). We have developed a computational approach (Transistion State Analysis) that models intermediate conformational states as receptors are activated. Our method accurately predicted efficacy and bias of drugs at two GPCRs. Prior to commercialisation, we need to validate our methods using a wider range of therapeutic targets and drugs. This technology will accelerate drug discovery, saving time and money, and have significant end-user impact.