Reviews & Analysis

Over the past decade, the drug–target residence time model has been broadly applied to drug discovery programmes across multiple therapeutic areas. To mark the 10 year anniversary of this model, Copeland discusses the benefits of assessing residence time, highlighting some of the advances in its theory and application.

A new model for translational research and drug repositioning has recently been established based on three-way partnerships between public funders, the pharmaceutical industry and academic investigators. This article discusses the progress with two pioneering initiatives — one involving the UK Medical Research Council and one involving the US National Center for Advancing Translational Sciences — and the unique requirements and challenges for this model.

Drug resistance is threatening to sideline the currently available antibiotics, and new antibiotics are unlikely to become available before the current arsenal becomes ineffective. Brown proposes the use of approved drugs or neutraceuticals as antibiotic resistance breakers — compounds that could be administered alongside current antibiotics to prolong their useful lifespan — to bridge the gap.

The quality of the chemical starting points for small-molecule drug discovery is a key factor in improving the likelihood of clinical success. In this article, experts from several organizations involved in drug discovery for malaria, tuberculosis and neglected tropical diseases present disease-specific criteria for hits and leads, and discuss the underlying rationale.

Incentives are increasingly available for the development of new drugs to tackle antibiotic resistance, but major scientific challenges remain, such as achieving penetration into bacteria. Tommasi and colleagues describe AstraZeneca's experiences in antibacterial drug discovery over the past decade using both target-based and phenotypic screening approaches, and discuss the reasons for failure as well as strategies to improve cytoplasmic penetration.

Epigenetic mechanisms of gene regulation have an important role in brain development, and evidence is accumulating that some neurological, psychiatric and behavioural disorders can be triggered or maintained by epigenetic means. In this Perspective article, Moshe Szyf explores the epigenetic basis of disorders of the central nervous system (CNS) and discusses strategies for the development of epigenetic-targeted drugs for CNS indications, as well as the particular challenges associated with this approach.

Efficient and reliable ways to predict drug metabolism early in the drug discovery process are important in reducing the risk of costly later-stage attrition. Schneider and colleagues summarize the state of the art in experimental and computational approaches for investigating drug metabolism, and discuss strategies to harness the potential synergies between them.

Thermodynamic profiling of protein–ligand binding is increasingly used during lead optimization to find ligands that bind with high affinity. In this Perspective, Gerhard Klebe discusses the importance of water, hydrogen bonds, lipophilic contacts and residual mobility in protein–ligand binding, and considers how knowledge of the influence of these factors on the enthalpic and entropic components of the resulting thermodynamic signature can be used in drug design.

Drug delivery methods that use targeted polymeric nanoparticles have the potential to increase local concentrations of a drug while reducing off-target accumulation. To best achieve this goal, Saltzman and colleagues argue that a holistic approach should be taken, in which anatomical, molecular and temporal aspects of the nanoparticle, drug and disease are taken into consideration.