Series 01 January 2003

A guide to drug discovery

Articles in this series provide an accessible discussion of a particular aspect of the process of turning ideas into drugs. The aim is to allow readers with limited knowledge of a given area to become familiar with the key concepts and techniques involved. Written by those closely involved in the discovery process, these articles aim to provide insights that will aid in future drug discovery programs.

Content

Screening out irrelevant cell-based models of disease

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.
- Peter Horvath
- Nathalie Aulner
- Neil O. Carragher
Opinion12 Sep 2016 Nature Reviews Drug Discovery
Mitigating risk in academic preclinical drug discovery

The recent growth in the number of academic drug discovery centres is providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclinical drug discovery practices used in industry. To realize the potential of these opportunities, it is important that academic researchers understand the risks in several key areas — including organization, target selection, assay design, medicinal chemistry and preclinical pharmacology — which are discussed in this article.
- Jayme L. Dahlin
- James Inglese
- Michael A. Walters
Review Article1 Apr 2015 Nature Reviews Drug Discovery
Validating therapeutic targets through human genetics

Many clinical trial failures can be traced back to the limited predictive value of preclinical models of disease. Plenge and colleagues discuss how knowledge from human genetics, such as naturally occurring mutations in humans that affect the activity of particular proteins, can be used as a tool to more effectively prioritize molecular targets in drug development.
- Robert M. Plenge
- Edward M. Scolnick
- David Altshuler
Review Article19 Jul 2013 Nature Reviews Drug Discovery
Emerging paradigms in GPCR allostery: implications for drug discovery

Allosteric ligands bind to G protein-coupled receptors at a site distinct from the endogenous ligand. This Review discusses the potential advantages that allosteric ligands could hold, and highlights how the complexity of their actions provides both challenges and opportunities for drug screening.
- Denise Wootten
- Arthur Christopoulos
- Patrick M. Sexton
Review Article1 Aug 2013 Nature Reviews Drug Discovery
Animal models for metabolic, neuromuscular and ophthalmological rare diseases

Animal models are vital tools in the development of therapies for orphan diseases, given the small populations of patients available to evaluate the therapies. Here, Sepodes and colleagues from the European Medicines Agency's Committee for Orphan Medicinal Products harness their experience to provide an overview of the animal models used to support regulatory applications for metabolic, neuromuscular and ophthalmological rare diseases.
- Guillaume Vaquer
- Frida Rivière Dannerstedt
- Bruno Sepodes
Review Article15 Mar 2013 Nature Reviews Drug Discovery
Reducing safety-related drug attrition: the use of in vitro pharmacological profiling

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.
- Joanne Bowes
- Andrew J. Brown
- Steven Whitebread
Opinion30 Nov 2012 Nature Reviews Drug Discovery
The determination and interpretation of the therapeutic index in drug development

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.
- Patrick Y. Muller
- Mark N. Milton
Opinion31 Aug 2012 Nature Reviews Drug Discovery
Finding the sweet spot: the role of nature and nurture in medicinal chemistry

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.
- Michael M. Hann
- György M. Keserü
Opinion30 Apr 2012 Nature Reviews Drug Discovery
Cell death assays for drug discovery

Dysregulated cell death occurs in many human diseases, and modulating the associated pathways has proved effective in the treatment of cancer, stroke and neurodegenerative disorders. In their review, Kepp and colleagues provide an overview of assays capable of accurately quantifying distinct cell death pathways, focusing on those techniques that are applicable to high-throughput screening.
- Oliver Kepp
- Lorenzo Galluzzi
- Guido Kroemer
Review Article1 Mar 2011 Nature Reviews Drug Discovery
The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery

Data on the fraction of protein-bound drug are frequently used to guide chemical structure design and to prioritize compounds forin vivostudies. Here, the authors highlight how these practices are misleading and could result in the wrong compounds being progressed through discovery programmes.
- Dennis A. Smith
- Li Di
- Edward H. Kerns
Opinion1 Dec 2010 Nature Reviews Drug Discovery
The future of drug development: advancing clinical trial design

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.
- John Orloff
- Frank Douglas
- Howard Golub
Opinion9 Oct 2009 Nature Reviews Drug Discovery
New approaches to drug safety: a pharmacovigilance tool kit

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.
- Lesley Wise
- John Parkinson
- Alasdair Breckenridge
Opinion18 Sep 2009 Nature Reviews Drug Discovery
Multi-parameter phenotypic profiling: using cellular effects to characterize small-molecule compounds

Here, the authors summarize the current state of multi-parameter profiling technologies and how phenotypic profiling of small molecules provides important insights into their mechanisms of action, as well as a systems level understanding of biological pathways and their responses to drug treatments.
- Yan Feng
- Timothy J. Mitchison
- John A. Tallarico
Review Article1 Jul 2009 Nature Reviews Drug Discovery
Typical pitfalls in applications for marketing authorization of biotechnological products in Europe

Despite improvements in European regulatory standards and procedures, the occurrence of failed or problematic marketing authorization applications for biotechnological products remains common. Here, Schäffner-Dallmann and Schneider identify common regulatory concerns and consider strategies that may help prevent such issues.
- Christian K. Schneider
- Gabriele Schäffner-Dallmann
Opinion1 Nov 2008 Nature Reviews Drug Discovery
High-throughput electrophysiology: an emerging paradigm for ion-channel screening and physiology

Ion channels remain an under-exploited drug target class owing to the low-throughput nature of patch-clamp electrophysiology. In this Review, Dunlop and colleagues evaluate automated electrophysiology platforms and discuss their impact in terms of ion-channel screening, lead optimization and the assessment of cardiac ion-channel safety liability.
- John Dunlop
- Mark Bowlby
- Robert Arias
Review Article1 Apr 2008 Nature Reviews Drug Discovery
Protein therapeutics: a summary and pharmacological classification

The number and frequency of use of protein therapeutics has increased dramatically since the introduction of the first recombinant protein therapeutic — human insulin — 25 years ago. Golan and colleagues overview some of the key characteristics of protein therapeutics, summarize the more than 130 protein therapeutics used currently and suggest a new classification of these proteins based on their pharmacological action.
- Benjamin Leader
- Quentin J. Baca
- David E. Golan
Opinion1 Jan 2008 Nature Reviews Drug Discovery
The application of discovery toxicology and pathology towards the design of safer pharmaceutical lead candidates

Toxicity is a leading cause of attrition at all stages of the drug development process. In their Review, Kramer and colleagues discuss how the early application of preclinical safety assessment can aid the design of safer pharmaceutical lead candidates.
- Jeffrey A. Kramer
- John E. Sagartz
- Dale L. Morris
Review Article1 Aug 2007 Nature Reviews Drug Discovery
Bayesian clinical trials

Bayesian statistical methods are being increasingly used in clinical research owing to the advantages they can offer compared with conventional approaches. Berry explains the underlying rationale, and discusses the potential of Bayesian trials to improve the effectiveness of drug development.
- Donald A. Berry
Review Article1 Jan 2006 Nature Reviews Drug Discovery
Pricing medicines: theory and practice, challenges and opportunities
- Nigel Gregson
- Keiron Sparrowhawk
- John Paul
Review Article1 Feb 2005 Nature Reviews Drug Discovery
The role of the medicinal chemist in drug discovery — then and now
- Joseph G. Lombardino
- John A. Lowe III
Review Article1 Oct 2004 Nature Reviews Drug Discovery
Virtual drug discovery and development for neglected diseases through public–private partnerships
- Solomon Nwaka
- Robert G. Ridley
Science and Society1 Nov 2003 Nature Reviews Drug Discovery
Protecting your inventions: the patent system
- Philip M. Webber
Review Article1 Oct 2003 Nature Reviews Drug Discovery
Trends in development and approval times for new therapeutics in the United States
- Janice M. Reichert
Review Article1 Sep 2003 Nature Reviews Drug Discovery
Logistics of process R&D: transforming laboratory methods to manufacturing scale
- Hans-Jürgen Federsel
Review Article1 Aug 2003 Nature Reviews Drug Discovery
Making Better Drugs: Decision Gates in Non-Clinical Drug Development
- J. Fred Pritchard
- Malle Jurima-Romet
- Mitchell N. Cayen
Review Article1 Jul 2003 Nature Reviews Drug Discovery
Predicting therapeutic value in the lead optimization phase of drug discovery
- Terry Kenakin
Review Article1 Jun 2003 Nature Reviews Drug Discovery
Hit and lead generation: beyond high-throughput screening
- Konrad H. Bleicher
- Hans-Joachim Böhm
- Alexander I. Alanine
Review Article1 May 2003 Nature Reviews Drug Discovery
Designing screens: how to make your hits a hit
- W. Patrick Walters
- Mark Namchuk
Review Article1 Apr 2003 Nature Reviews Drug Discovery
Combinatorial compound libraries for drug discovery: an ongoing challenge
- H. Mario Geysen
- Frank Schoenen
- Richard Wagner
Review Article1 Mar 2003 Nature Reviews Drug Discovery
Modern biomedical research: an internally self-consistent universe with little contact with medical reality?
- David F. Horrobin
Opinion1 Feb 2003 Nature Reviews Drug Discovery
Target selection in drug discovery
- Jonathan Knowles
- Gianni Gromo
Review Article1 Jan 2003 Nature Reviews Drug Discovery

A guide to drug discovery

Content

Screening out irrelevant cell-based models of disease

Mitigating risk in academic preclinical drug discovery

Validating therapeutic targets through human genetics

Emerging paradigms in GPCR allostery: implications for drug discovery

Animal models for metabolic, neuromuscular and ophthalmological rare diseases

Reducing safety-related drug attrition: the use of in vitro pharmacological profiling

The determination and interpretation of the therapeutic index in drug development

Finding the sweet spot: the role of nature and nurture in medicinal chemistry

Cell death assays for drug discovery

The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery

The future of drug development: advancing clinical trial design

New approaches to drug safety: a pharmacovigilance tool kit

Multi-parameter phenotypic profiling: using cellular effects to characterize small-molecule compounds

Typical pitfalls in applications for marketing authorization of biotechnological products in Europe

High-throughput electrophysiology: an emerging paradigm for ion-channel screening and physiology

Protein therapeutics: a summary and pharmacological classification

The application of discovery toxicology and pathology towards the design of safer pharmaceutical lead candidates

Bayesian clinical trials

Pricing medicines: theory and practice, challenges and opportunities

The role of the medicinal chemist in drug discovery — then and now

Virtual drug discovery and development for neglected diseases through public–private partnerships

Protecting your inventions: the patent system

Trends in development and approval times for new therapeutics in the United States

Logistics of process R&D: transforming laboratory methods to manufacturing scale

Making Better Drugs: Decision Gates in Non-Clinical Drug Development

Predicting therapeutic value in the lead optimization phase of drug discovery

Hit and lead generation: beyond high-throughput screening

Designing screens: how to make your hits a hit

Combinatorial compound libraries for drug discovery: an ongoing challenge

Modern biomedical research: an internally self-consistent universe with little contact with medical reality?

Target selection in drug discovery

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