Future Horizons in Drug Discovery Research

Where early stage drug discovery research occurs will return to the world of 1912 and Paul Ehlrich, with most basic innovation taking place in the public sector such as at universities and nonprofit research institutions. Capital intensive preclinical and clinical drug development will continue to be done by the for-profit organizations that can exploit networks of production, distribution, and marketing. This trend is obviously in full force now, as large pharmaceutical companies are reducing their early drug discovery research operations. Numerous drug discovery centers have emerged in the public sector primarily at universities, attempting ostensibly to capitalize on the funding to be achieved by licensing products externally while taking advantage of internal innovation. The tools and processes involved in drug discovery are now more of an off-the-shelf commodity-driven operation than previously. The more productive chemists in the department at the start of my career submitted 30 compounds per year; now, with the tools of parallel synthesis, it is common to prepare >200 compounds per year. Diversity is now more important in early library design and synthesis than fidelity in structure and purity of any particular member. Techniques such as fragment-based drug discovery in medicinal chemistry and high-content screening in pharmacology seek to produce more information while doing the same amount of work. As long as safe laboratory practices are followed, certain trained high school and undergraduate chemists can perform the work that some Ph.D.s were asked to do 10–15 years ago. Knowledge has become more of a commodity, as the Internet has allowed us to instantly create review-quality literature searches customized to any particular need.

The emphasis upon new treatments for communicable diseases such as malaria, HIV, and tuberculosis has been and is admirable. Relatively effective treatments currently exist to treat AIDS, with the greatest challenge being affordability and distribution. De novo drug discovery to treat diseases that have previously been truly neglected such as trypanosomiosis are getting more attention from the WHO and elsewhere. However, the WHO has recently additionally recognized that the NCDs such as cardiovascular disease, diabetes, cancer, respiratory diseases, and neurological disorders are now also a great emerging and emerging epidemic among the poor (Reardon, S.A World of Chronic Disease. Science 2011, 333, 558). Of the 57 million deaths occurring worldwide in 2008, 36 million (63%) were due to NCDs, of which 80% of these occurred in low- and middle-income countries. NCDs do not thus primarily afflict the first or developed world, they are primarily diseases of the developing world and will be much more so in the future. Mortality due to NCDs is projected to increase 15–20% worldwide to the year 2020, whereas mortality due to communicable diseases is projected to decrease in absolute numbers from the present time. As children are saved from dying of malaria, they grow up to most likely suffer from a NCD requiring chronic therapeutic intervention. The WHO convened a high-level meeting to address the NCD epidemic in September, 2011, only the second such meeting to be held, with the first one associated with HIV/AIDS.

More effective health care worldwide is resulting in increased life expectancies. Coupled with lower birth rates, populations of the future will have larger mean age values and numbers of elderly individuals. Chronic age-associated diseases such as Alzheimer's, diabetes, Parkinson's, macular degeneration, and ALS will increase in prevalence.

Over the course of the next 100 years, release of radioactivity to large patient populations such as at Fukushima, Japan, may occur due to terrorist attacks, a full-scale or partial nuclear engagement during conflict, or by accident. There are currently four drugs with approved INDs for acute radiation syndrome (ARS), to ameliorate the effects of ionizing radiation after exposure. A prevalent molecular mechanism for radioprotection is to protect mitochondria from reactive oxygen species damage, such as by GSK-3β inhibition, a very similar therapeutic modality as for treatment of many of the neurological disorders. Radioprotective agents are also useful for the protection of normal tissue against collateral damage in radiation oncology.

We have now passed the milestone of 7 billion persons on planet earth. In spite of hunger and deprivation in parts of the world, it is remarkable that most of humanity has adequate food and shelter. The UN projects that using a “medium-fertility variant” of 2.0 children per woman, the population on earth will reach 10 billion by the year 2100 ( Science 2011, 333, 540). A medium variant of 2.5 children per woman results in 15 billion persons in 2100. The resources on earth, while substantial, are limited, and over the next 100 years, we will have passed the projected midpoint of the extraction of readily available sequestered carbon sources to power our fuel-based economy. It is most likely that communities of the future will rely to a greater extent than now on local production for local consumption. The effect on drug discovery research is that cost of goods will be a greater component to drug candidate selection than before. It may not be possible to charge the equivalent of $20,000 per year for a costly treatment regimen for large patient populations, especially for the NCDs for which chronic treatment over many years is required. Under current patent law, by the year 2112, every drug whose patent was filed before 2091 will be generic. Some have suggested that the way in which new compositions are protected by monopoly-granting patents for diseases should be abandoned or modified, especially for the neglected diseases for which there is limited commercial return. Low cost chemical production coupled with efficient quality control and distribution will be the essential elements of our ability in the future to treat the large fraction of humanity that will not be able to afford more expensive treatment options. Combination therapy with cheaper complementary and alternative natural remedies may help to promote wider availability of therapeutic relief options.

It is well understood that the climate is warming and the oceans are rising. The apparent impact of these trends on drug discovery will be a greater prevalence of the tropical diseases such as typhus and malaria. Although this is true, as long as vector control such as for lice and mosquitos continues as a high priority, these diseases should not spread dramatically.

Personalized medicine is expected to be more prevalent in the future, with genotypic screening to precede drug treatment. More accurate dosing should occur based upon real-time monitoring of exposure and understanding of the relative propensity for drug metabolism in any particular patient. The exploitation of new chemical scaffolds would be based on the structure elucidation of natural products yet to be identified. Atypical targets such as the protein–protein interface and nucleic acid binding transcriptional regulators will be more prevalent, as will the use of phenotypic screening and induced pluripotent stem cells in research. Protein- or gene-based approaches may gain greater acceptance. Nanotechnology as well as the use of molecular motors for tissue repair on a microscopic level could emerge as complementary to small-molecule and biologic therapy. Then, there is the “Who can possibly predict?” factor, for revolutionary new developments currently not anticipated. Science is great fun, and the “unexpected” is the driving force of new discovery.