BioWorld Perspectives Contributing Writer

Editor's note: Mike Williams is adjunct professor at Northwestern University in Chicago, from where he publishes his personal views on today's drug discovery industry.

For the better part of the past three decades, interest in natural products as potential sources for new drugs has been overshadowed by an overtly mechanistic, targephilic approach to identifying new chemical entities (NCEs) as potential leads for new drugs.

The Targephilic Approach
This approach involves the screening, via high-throughput screening (HTS), of libraries of small molecules in massive numbers against selected targets expressed in vitro. This is done in anticipation of identifying NCEs active at a discrete molecular target that could be optimized for potency, efficacy, selectivity and drug-like properties.

Since these NCEs would ostensibly be selective in their target interactions, it was an a priori assumption that their side effect liabilities would be reduced if not eliminated. Drug discovery would thus become faster and more cost effective. This approach was supported by robotics-based HTS assay systems and by newer chemistry technologies, covered under the rubric of "combichem," which involved the facile synthesis on an industrial scale of thousands to millions of compounds. A focus on making compounds that could be made rather than those that should be made markedly limited the useful contributions from combichem such that it now has been replaced by the infinitely more productive parallel library synthesis approach, with a greater emphasis on NCEs that have drug-like properties.

To many in the pharmaceutical industry, the reductionistic nature of the targephilic approach played a major role in the dearth of new drug approvals. This is reflected in the comment attributed to Martin MacKay, Pfizer Inc.'s head of research, after the January 2009 layoff of 800 researchers that "nobody in the industry is happy with our productivity."

It also can be seen in New York-based Pfizer's subsequent acquisition of Wyeth for a record $68 billion, with five-figure layoffs in the offing. Pharma now is in the throes of necessarily rediscovering a more holistic, pharmacology-based approach to drug discovery. Not so the federal government.

The NIH Roadmap
In 2003, the NIH Roadmap Initiative established the Molecular Libraries Initiative (MLI) to facilitate the use of HTS to identify small molecules and to study cellular pathways "in health and disease by rapidly and efficiently screening a large number of compounds that encompasses a broad range of novel targets and activities." It aimed to increase the number of molecules available as potential drug candidates for further development by both the public and private sectors.

The MLI funded some nine screening centers in academia to do precisely what the pharma industry had concluded, after 25 years of real world experience, was a somewhat futile exercise. As of 2008, the MLI initiative had produced a number of interesting papers together with 62 NCE "probes."

Since the MLI reportedly would not fund in vivo testing, these NCEs frequently lacked adequate functional efficacy, in vivo and ADME/safety data for them to be considered as anything more than test tube curiosities. It led industry scientists (quoted in Science in August 2008) to ask "whether this massive effort is worth the time and money" or more pithily, using an acronym born of the Internet, whether it is actually a WOMBAT (waste of money, brains and time).

The NIH's Contributions to Drug Discovery
In Michael Moore's thought-provoking documentary film Sicko, outspoken pharma industry critic Marcia Angell noted that "very little ... innovative research is done by big pharma ... The real conceptual leaps are in universities and the NIH."

Industry scientists engaged in innovative research, including several Nobel laureates, took issue with the accuracy and fairness of Angell's comments since the MLI, the current flagship of the NIH Roadmap, can be considered as being anything but innovative.

Nonetheless, basic intramural research at the NIH has added immeasurably to drug discovery in ways that would be unthinkable in industry. One example of this is the work of John Daly, a medicinal chemist at the NIH for nearly 50 years who died last year and has been described by his NIH colleagues as "legendary and irreplaceable." Daly spent his life's work studying alkaloids from natural product sources, including coffee and frogs with numerous field trips to the Amazon, Ecuador, Madagascar and other exotic climes the latter leading to him being described as the "Indiana Jones of the NIH."

From these, Daly made two key discoveries. The first was the discovery of the adenosine A_2a receptor at which caffeine, the active ingredient in coffee, produces some of its biological effects. Subsequent findings by researchers at the Karolinska Institute established that antagonists for this receptor had potential in the treatment of Parkinson's disease (PD).

Additional support for this hypothesis came from data from the prospective Honolulu Heart Program, funded by the NIH in 1965 to study the environmental and biological causes of cardiovascular disease in Japanese Americans living in Hawaii. This showed that "higher coffee and caffeine intake is associated with a significantly lower incidence of PD."

Additionally, a January 2009 Scandinavian study reported that individuals drinking three to five cups of coffee a day were 65 percent less likely to develop dementia than those who drank two cups a day or less. Of several A_2a receptor antagonists advanced to clinical trials, the first, istradafylline, failed to show efficacy in a pivotal Phase III trial. More potent and selective compounds from Biogen and Schering-Plough, however, are now in advanced PD trials.

Individual's Roadmaps Prove Wombat Theory Wrong
Daly's work complimented and reinforced established research on nicotinic receptors ongoing at Abbott Park, Ill.-based Abbott and Winston-Salem, N.C.-based Targacept Inc. that led to more selective compounds now in Phase II clinical trials for pain. (It is noteworthy that the publicity related to Abbott's first-generation nicotinic analgesic, ABT-594, was the inspiration for Paul Simon's 2000 song "Senorita With a Necklace of Pearls," which noted "a frog in South America has the antidote to pain.")

Both adenosine A_2a receptor antagonists and neuronal nicotinic receptor agonists are potentially first-in-class medications for the treatment of PD and pain. These visible contributions from coffee and frogs to the drug discovery process contrasts with those dependent on "wombats," clearly demonstrating that 1) individual scientists can create their own Roadmaps, and 2) natural products still have untapped utility in treating human disease.

As biomedical research in China and India becomes more sophisticated with a better understanding of the molecular actions of the natural products used for thousands of years as therapeutics, this trove of new information will add to Daly's legacy and improve drug discovery metrics. Indeed, drug treasures still potentially exist in the NIH sample collection (the Daly Collection) that his colleagues continue to work on.

Published: February 26, 2009