Drug discovery in the 21st century

A sea change in knowledge, technology… and collaboration

Jeffrey Conn, Ph.D
Lee E. Limbird Professor of Pharmacology
Director, Program in Drug Discovery
Vanderbilt University Medical Center
Published: July, 2005

P. Jeffrey Conn, Ph.D.
Photo by Dean Dixon
Over the past decade, we have witnessed unparalleled advances in our understanding of basic biological processes that contribute to a host of human disorders. The highly celebrated elucidation of the sequence of the human genome and other technological gains have allowed identification of a broad range of regulatory proteins and complex signaling systems that play critical roles in a variety of normal physiological processes as well as pathological conditions in virtually all major organ systems.

Today we have an understanding of the mechanisms underlying complex human disorders such as Alzheimer’s disease, diabetes, multiple cancers, schizophrenia, and many others. These key new insights may provide paths to fundamental advances in care or even cures for patients suffering from these disorders.

Translation of this new knowledge into practical gains in health care has moved more slowly, despite the recent doubling of the National Institutes of Health budget, and a 16-fold increase in research-and-development spending by pharmaceutical companies between 1980 and 2002. Many of the drugs currently available were developed before the 1950s, prior to the recent expansion in our understanding of the basic biology underlying human disorders.

Recent years have seen a steady decline in the number of new drugs approved for clinical use, and many of the recent approvals represent subtle changes to existing medications, providing incremental rather than fundamental advances in therapeutic strategies. The decrease in introduction of fundamentally new drugs into clinical practice during a time of increased knowledge and increased research spending stems in part from a fundamental shift in the basic paradigms used for drug discovery.

In the early drug discovery era, novel therapeutic agents were derived from known compounds, often plant extracts, which had medicinal properties. The major goal was to isolate the therapeutic component of the plant and refine it by making relatively modest chemical modifications.

Investment was often made with no understanding of the basic mechanism of the drug’s action, although there was existing knowledge that the compound had properties that allowed it to reach the target organ and have clinical efficacy. Also, there was some level of understanding of the potential toxicity based on clinical experience with the plants from which the compound was derived. Because of this, the risk that a drug discovery program would fail was relatively low.

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