Opinion

Analysis of the role of synthetic organic chemistry in the identification of chemical starting points for drug discovery and subsequent optimization into candidate drugs indicates that a small number of reactions and commercially available building blocks dominate. This Perspective highlights opportunities for expanding the synthetic toolbox of medicinal chemists, potentially enabling the more effective exploration of therapeutically relevant chemical space.

Dysregulation of the endocannabinoid system has been implicated in numerous diseases, particularly pain, psychiatric and neurological disorders, but therapeutic intervention in this complex system has proved challenging. In this Perspective article, Di Marzo discusses the lessons learned from the development of drugs that alter endocannabinoid signalling and highlights novel opportunities for pharmacologically manipulating the endocannabinoid system, such as the use of multi-target drugs.

Recent studies have indicated the potential to develop small-molecule drugs that act on RNA targets, leading to burgeoning interest in the field. This article discusses general principles for discovering small-molecule drugs that target RNA and argues that the overarching challenge is to identify appropriate target structures in disease-causing RNAs that have high information content and, consequently, appropriate ligand-binding pockets.

There has been a resurgence in interest in phenotypic drug discovery (PDD) approaches in recent years based on their potential to address the incompletely understood complexity of diseases and their promise of delivering first-in-class drugs. However, PDD approaches can also present considerable challenges, and this article focuses on the lessons learned by researchers engaged in PDD in the pharmaceutical industry, and discusses how PDD can best deliver value to drug discovery portfolios.

Traditional cell-based disease models often fail to adequately represent key disease characteristics, increasing the risk of subsequent attrition in clinical trials. This article presents a set of principles for disease-relevant assays, and discusses new opportunities for exploiting advances in cell-based assay technologies in drug discovery, including induced pluripotent stem cells as well as 3D co-culture and organ-on-a-chip systems, which are being complemented by progress with single-cell imaging and gene editing technologies.

Non-coding RNAs (ncRNAs) may affect normal gene expression and disease progression, thereby representing potential drug targets. Here, Matsui and Corey assess the potential and challenges in therapeutically exploiting ncRNA species — including microRNA, intronic RNA, repetitive RNA and long ncRNA — highlighting key lessons learned during the development of technologies targeting mRNA.

This article discusses evolving preclinical strategies for detecting drug-induced cardiotoxicity using human ion-channel assays, human-basedin silicoreconstructions and human stem cell-derived cardiomyocytes. Such strategies have the potential to improve the early detection of genuine cardiotoxicity risks, reducing the likelihood of mistakenly discarding viable drug candidates and speeding worthy drugs into clinical trials.

Members of the integrin family of receptors, which are involved in cell–cell adhesion, have been successfully targeted for cardiovascular disease, multiple sclerosis and inflammatory bowel disease. Ley and colleagues review the biological basis for the development of the next generation of integrin-targeted drugs, highlighting lessons learned from successes and failures.

Modulators of glucagon-like peptide 1 (GLP1) and the resulting G protein-coupled receptor (GPCR) signalling have recently come to the fore of the treatment of type 2 diabetes. In this Opinion article, Oh and Olefsky discuss the potential for intervention with other GPCRs for the treatment of this disease, highlighting GPCR-mediated effects on insulin secretion, insulin sensitivity and inflammation.

The conversion of cells with an epithelial phenotype into cells with a mesenchymal phenotype — epithelial–mesenchymal transition — has a key role in tumour progression and is therefore becoming a promising anticancer target. This article discusses the screening and classification of compounds that affect epithelial–mesenchymal transition, highlights some compounds of particular interest and discusses issues related to their clinical application.

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.

Potential drug–drug interactions mediated by ATP-binding cassette (ABC) and solute carrier (SLC) transporters are of clinical and regulatory concern, but the endogenous function of these drug transporters is unclear. Nigam describes the evidence that these transporters transport diverse endogenous substrates and could potentially be important in remote communication. Understanding such functions could clarify the roles of these transporters in disease and in drug–metabolite interactions.