Reviews & Analysis

The GPCR Network was established in 2010 with the aim of structurally characterizing 15–25 representative human G protein-coupled receptors (GPCRs) within 5 years; so far, more than eight have been determined. Here, Stevens and colleagues provide an overview of this collaborative effort and the challenges remaining in gaining detailed insights into the structure–function relationships of this receptor superfamily.

In vitropharmacological profiling is playing an increasing part in identifying undesirable off-target effects of candidate drugs earlier in the drug discovery process. In this article, authors from four large pharmaceutical companies share their views on the rationale, strategies and methodologies forin vitropharmacological profiling, and recommend a minimal panel of targets for screening.

Preclinical research indicates that various drugs approved for indications such as hypertension and diabetes could also have potentially beneficial effects in Alzheimer's disease, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. This article presents a formal consensus evaluation of these drug repositioning opportunities, and highlights several compounds for which sufficient evidence is available to encourage further investigation and potential progression to clinical trials in Alzheimer's disease.

The therapeutic index of drug candidates — a quantitative relationship between their safety and efficacy, such as the ratio of the highest exposure to a drug that does not cause toxicity to the exposure that has the desired pharmacological effects — is widely used to aid decision-making in drug discovery and development. Muller and Milton discuss key issues in the calculation and interpretation of therapeutic indices at different stages of the process.

Here, Lawson proposes that the use of antibodies as tools in small-molecule drug discovery — for example, to validate targets, enable crystallography and to constrain proteins for screening — could reduce risks and facilitate the modulation of traditionally intractable targets, such as protein–protein interactions.

Extensive analyses of successful and failed compounds in drug discovery and development have improved our understanding of the role of physicochemical properties in attrition. They have also clarified the difficulties in finding the 'sweet spot' in medicinal chemistry programmes. Hann and Keserü discuss scientific, strategic and cultural considerations for medicinal chemistry practices, with the aim of promoting more effective use of what is already known, and a wider appreciation of the risks of pursuing suboptimal compounds.

The number of new drugs approved per billion US dollars spent on research and development (R&D) has fallen around 80-fold in inflation-adjusted terms since 1950, despite advances in many of the scientific and technological inputs into the R&D process. Given the apparent lack of impact of proposed solutions to declining R&D efficiency so far, Scannell and colleagues ask whether the underlying problems have been correctly diagnosed and discuss factors that they consider to be the primary causes.

Biased ligands of seven-transmembrane receptors (also known as GPCRs), which preferentially activate specific signalling pathways associated with a given seven-transmembrane receptor (GPCR), could have novel therapeutic profiles. Here, the authors discuss which methods may be most appropriate to quantify bias in a drug discovery setting.

This Perspective highlights the sources and functions as well as the evaluation of biomarkers that are useful in cancer, with a focus on those biomarkers that are most relevant for identifying patients who are likely to respond to a given therapy, and those biomarkers that are most effective for measuring patient response to therapy.