Reviews & Analysis

Proteomics techniques can be applied in drug target identification and validation, but data interpretation can be complicated by the identification of proteins in unexpected cellular locations. Here, Butler and Overall discuss the importance of recognizing that many intracellular proteins may have physiological functions in the extracellular compartment, and its implications for drug discovery.

The emerging resistance to current antimalarial drugs calls for new strategies to control the disease. This article highlights the potential of targeting the obligate short-lived hepatic forms of the malaria parasite and ways to overcome the challenges of developing drugs that will achieve this.

Orloff and colleagues describe how moving from the traditional approach to clinical trials based on sequential, distinct phases towards a more integrated strategy that increases flexibility and maximizes the use of accumulated knowledge could have a key role in improving the efficiency and cost-effectiveness of drug development. Using examples in which novel trial designs have been successfully applied, they also illustrate the use of the tools involved, such as Bayesian methodologies, and discuss the advantages and challenges for their more widespread implementation.

The need to manage drug safety issues is an increasingly common feature of drug research, regulation and prescription. This article discusses several key areas for development that could deliver long-term solutions to drug safety challenges: enhanced tools for the detection of safety signals, innovative phased drug launches, new risk stratification techniques and improved pharmacovigilance operations.

The importance of pharmacovigilance — the ongoing assessment of the safety of a marketed medicine — has been increasingly appreciated in recent years. Breckenridge and colleagues summarize the key tools that are available for pharmacovigilance, discuss which might be the most appropriate to use in different situations and consider the future directions of the field.

The focus for the use of bioinformatics resources in the pharmaceutical industry is increasingly moving from the vigorous pursuit of intellectual property towards exploration of pre-competitive collaborations and engagement with the public domain. In this article, we discuss the rationale for these changes and the associated challenges, and also propose new areas of public–private collaboration in computational biology and chemistry that could enhance drug discovery in academia and industry.

Here, Kenakin discusses how the efficacy of drugs that act at seven-transmembrane receptors is linked to the particular pharmacological assay used to observe the effects of the drug, and highlights how a return to whole–system assays is adding value to the drug discovery process.

More effective prediction of 'translational success' could have a key role in addressing the widely acknowledged problems with weak drug development pipelines. This article discusses how establishing a scoring system to systematically assess key determinants of translational success, such as biomarkers and animal and human data, could help achieve this goal.

Cardiovascular disease associated with type 2 diabetes has become a major issue in the development of new diabetes therapies. DeSouza and Fonseca review the background to and implications of recent regulatory guidance for cardiovascular risk assessment of new antidiabetic agents, and discuss the potential beneficial cardiovascular effects of selected agents currently in development.

Large-scale generation and integration of genomic, proteomic and metabolomic data are increasingly allowing the construction of complex networks that provide a new framework for understanding the molecular basis of disease states. This Opinion article highlights how this knowledge could be applied to network-based drug discovery to investigate the impact of interventions — such as candidate drugs — on the molecular networks that define these states, and could ultimately be used to develop improved therapies.

Recent clinical trials have raised questions about the perceived advantages of second-generation 'atypical' antipsychotics over older drugs. This article discusses how broadening of the concept of 'atypicality' — originally related purely to a lack of extrapyramidal side effects — might have hampered the search for better antipsychotics, and proposes that redefining the concept could be key for breakthroughs in schizophrenia therapy.

The nuclear factor κB (NF-κB) signalling pathway has been implicated in cancer development and progression, as well as in resistance to chemotherapy and radiation therapy. In this Perspective, Baud and Karin explore the therapeutic potential of targeting NF-κB in cancer, and discuss the challenges posed by this approach.