Enabling Technologies in Drug Discovery: The Technical and Cultural Integration of the New with the Old

Abstract

For the better part of the past two decades, activities related to drug discovery have been technically enabled by a wealth of sophisticated research tools that have: (1) the ability to produce many more new chemical entities (NCEs) using parallel synthesis chemical techniques than has ever been previously possible; and (2) the ability to assay the activity and selectivity of these NCEs in both recombinant and native biological systems and to interrogate this information using bioinformatics tools. If the process of drug discovery were to be viewed solely in terms of ‘numbers,’ where characterizing more compounds in more assay systems were the end game, then the application of these technologies should have resulted in a major increase in the number of novel drugs entering clinical trials with a concomitant increase in drug approvals. This has clearly not been the case (at least not to date) and has led to questions as to whether these technologies have: (1) basic utility in the drug discovery process; (2) been appropriately used; and/or (3) had sufficient time to reach their full potential. In defense of the dearth of new drug approvals over the past decade, it has been argued that the targets now being addressed are far more sophisticated/complex than those that led to the current pharmacopoeia and that regulatory hurdles have become more difficult. It has also been argued, perhaps more cogently, that the drug discovery process and its underlying scientific base have become increasingly oversimplified as business considerations, driven by pharmaceutical marketing and biomedical venture capital that have intruded into the earlier stages of the process. As a consequence, drug discovery has become technologically, rather than intellectually, driven being viewed as a commodity where targets, disease states and even scientists are interchangeable, where time-lines are defined in terms of those of a production line, and where the cultures of innovation and serendipity historically intrinsic to biomedical research have been devalued or ignored. Thus, the search for answers to important problems has frequently assumed second place to efforts to find uses for unproven, expensive, and in many circumstances, irrelevant, technologies that promised much but have, to date, delivered little. Rather than synergizing with existing approaches with proven success records, the technological approach has naively tended to exclude proven core disciplines, most notably that of pharmacology, that provide an integrated, multidisciplinary approach to the drug discovery process and which has been the sister discipline to that of medicinal chemistry. This trend is interestingly reminiscent of what occurred when combinatorial chemistry sought to replace traditional medicinal chemistry as the source of new compounds. Rather than reinventing pharmacology under such phrases as chemical genomics, systems biology, or translational therapeutics, the necessary path forward is to (re)place pharmacology and its sister discipline, medicinal chemistry, squarely in the middle of the drug discovery process where new technologies can then be used, with leadership well versed in, and focused on, drug discovery, in a synergistic manner to ask questions and develop hypotheses in order to add value and increase productivity.