The reductionist paradox: are the laws of chemistry and physics sufficient for the discovery of new drugs?

Abstract

Reductionism is alive and well in drug-discovery research. In that tradition, we continually improve experimental and computational methods for studying smaller and smaller aspects of biological systems. Although significant improvements continue to be made, are our efforts too narrowly focused? Suppose all error could be removed from these methods, would we then understand biological systems sufficiently well to design effective drugs? Currently, almost all drug research focuses on single targets. Should the process be expanded to include multiple targets? Recent efforts in this direction have lead to the emerging field of polypharmacology. This appears to be a move in the right direction, but how much polypharmacology is enough? As the complexity of the processes underlying polypharmacology increase will we be able to understand them and their inter-relationships? Is "new" mathematics unfamiliar in much of physics and chemistry research needed to accomplish this task? A number of these questions will be addressed in this paper, which focuses on issues and questions not answers to the drug-discovery conundrum.

The future of molecular dynamics simulations in drug discovery

“…The bottom line is this: All experimental drugs enter human clinical trials based on extensive preclinical data indicating that they should work; most nonetheless do not, defying our well-grounded expectations. The complexities of human biology, amplified by the limitations of the reductionist paradigm of target-based drug discovery [16], thus appear to be our industry’s largest challenge.…”

Nicotinic ligands as multifunctional agents for the treatment of neuropsychiatric disorders

“…It has also become increasingly evident that the reductionist approach to modern drug discovery that has dominated the field for decades (i.e., the development of highly selective compounds or other treatment modalities focused on a very specific pathophysiologic target) has not been widely successful [5], especially for the treatment of neuropsychiatric disorders [6]. Accordingly, a number of alternative approaches to drug discovery have emerged and they include the development of “multitarget-directed ligands” (MTDLs) “multifunctional” compounds, “repurposing” strategies, and novel “adjunctive” treatment strategies.…”

Shifting from the single to the multitarget paradigm in drug discovery

“…Following the lock and key model proposed by Erlich more than a century ago [1], over the previous decades, drug discovery efforts have focused on identifying single selective drugs that target a single mechanism; that is, identifying ligands (‘keys’) that fit into specific targets (‘locks’) (Figure 1). This strategy has been largely motivated by the reductionist view of systems biology [2], aided by the ever-increasing understanding of biological processes at the molecular level (e.g. molecular interactions of a chemical compound with a target protein).…”