Innovation

Advances in areas such as microfluidics-assisted chemical synthesis and biological testing, as well as in artificial intelligence systems, are increasingly providing opportunities to introduce greater automation into the small-molecule drug discovery process. Schneider highlights approaches and technologies that seem poised to be implemented robustly by medicinal chemists in the near future and analyses the challenges for their more widespread application

Recent advances in areas such as natural product biosynthesis, synthetic biology and the development of biosensors are providing new opportunities to directly harness evolutionary pressure to identify and optimize compounds with desired bioactivities. This article describes innovations in the key components of such strategies, highlights pioneering examples that indicate their potential, and discusses the scientific gaps and challenges that remain to be addressed to realize this potential more broadly in drug discovery.

Microengineered cell culture systems are becoming sufficiently sophisticated that they can recapitulate many of the phenomena observed in tissues and organisms. Here, Huh and colleagues discuss the advances made in these 'organs-on-chips' and how they could be used in drug development, including target identification and validation, toxicity screening and stratified medicine.

Rapid advances in next-generation sequencing (NGS) are facilitating deeper insights into the molecular classifications of cancer and the mechanisms of resistance development, thereby paving the way for a new era of personalized medicine. In this Perspective, Simon and Roychowdhury explore how genomic information can be used in the design of clinical trials for molecularly targeted anticancer drugs as well as for the development of new biomarkers.

Extracellular vesicles have emerged as important mediators of intercellular communication, and they are now implicated in numerous biological and pathological processes. Here, Wood and colleagues focus on the role of extracellular vesicles in diseases including cancer, HIV and neurodegenerative disorders, and consider how extracellular vesicles might be targeted or directly exploited for therapeutic intervention.

Recent advances in stem cell technology are allowing the production of a variety of human cell types that could provide the basis for more effective drug screening for toxicity and efficacy, as well as more relevant disease modelling based on induced pluripotent stem cells derived from patients.

Isothermal titration calorimetry can be used to obtain thermodynamic data on the binding of compounds to protein targets. Ladbury and colleagues propose that these data — particularly the change in enthalpy — could be a valuable addition to established tools for selecting compounds in lead discovery and for aiding lead optimization.

The wealth of genomic data for pathogens that cause tropical diseases hold considerable promise for the discovery of novel drugs. An international consortium describes how the TDR Targets database integrates this data with related biochemical and pharmacological data to facilitate the identification and prioritization of drug targets.

High-throughput profiling of compound libraries against large panels of kinases is becoming technically feasible. In contrast to the traditional linear, target-centric approach to discovery, this approach may provide a choice of targets to pursue that is guided by the quality of lead compounds available, rather than by target biology alone, and could thereby significantly improve the productivity of kinase inhibitor discovery.

Embryonic stem cells (ESCs) can be used as a source of cellular models for a wide range of adult differentiated cells, providing that reliable differentiation protocols are established. Here, Pouton and Haynes discuss challenges and opportunities regarding the use of ESC-derived models for drug discovery.

The intrinsic robustness of biological systems is a key factor preventing the success of potential drugs that target specific molecules. Using examples based on existing drugs, Kitano discusses how a greater consideration of the importance of robustness could influence the design of new drugs intended to control complex systems.

Needle-free liquid jet injectors have been used for over five decades for delivery of numerous vaccines and drugs such as insulin, growth hormones and anaesthetics. Mitragotri reviews jet injectors with respect to their clinical and emerging applications, mechanistic understanding and future prospects.

Although the prospects of gene therapy have not been fully realised, there is hope that nanotechnologies will have great impact on this field. Crommelin and colleagues describe such approaches to gene therapy. Nucleic acid delivery systems are being developed that incorporate virus-like functions in a single nanoparticle.