2018/10/30 by Stuart L. Schreiber
Biochemistry, Genetics and Molecular Biology · #Protein Degradation and Inhibitors #Signaling Pathways in Disease #Ubiquitin and proteasome pathways
paper · doi:10.1002/ijch.201800113
crossref issued 2018/10/30 · crossref published 2018/10/30 · crossref published-online 2018/10/30 · openalex publication_date 2018/10/30 · crossref created 2018/10/30 · crossref published-print 2019/02/01 · crossref deposited 2023/09/07 · openalex created_date 2025/10/10 · crossref indexed 2026/08/01 · openalex updated_date 2026/08/02
A simplistic view of drug discovery is that it begins, most often using “model organisms”, with biological inferences of a disease that suggest the need to interfere with some activity, function or process. An enzyme should be inhibited or a pathogen should be killed. Chemical experimentation yields the desired inhibitor, and clinical investigations then test the underlying hypothesis in humans. If the stars align, an effective drug emerges. The high cost of testing and low rate of success of this paradigm has led the drug-discovery enterprise to search for new and more effective approaches. In this essay, I explore a concept that focuses on the discovery of compounds that bind targets rather than inhibit a biochemical activity. I present evidence that such ‘binders’ can affect protein activity in under-appreciated ways that have therapeutic potential. This approach is well aligned with a current trend in drug discovery – to exploit insights from human biology in order to select therapeutic targets with greater confidence and to understand the deficiencies of the targets that need correction. The targets emerging from this approach most frequently lack the “simple” activities that drive much of past drug discovery. Compounds are needed that engage these targets in new and challenging ways to elicit the novel activities suggested by human biology, especially enhancing functions of proteins and conferring new (neo) functions to proteins (Figure 1). Open in a separate window Figure 1 Topographically complex hot spots on proteins can be liganded with suitably shaped, often 3-D small molecules, which results in modulating functions in different ways. Binding alters the dynamic and structural features of proteins, resulting in: 1) novel interactions with other proteins and 2) changes in protein dynamics, stability, turnover rates, and tendency to be chemically modified by cellular enzymes. Each of these under-appreciated effects can have therapeutic consequences. In addition to the common use of binders to inhibit function, they can also restore or enhance function, or even create a new function. Achieving a framework of chemical biology that emulates nature and evolution, where nature evolves and optimizes not so much by losing functions, but by enhancing functions and inventing new ones, promises to unlock potential not only for eliminating disease states but also for enhancing and augmenting states of health and wellness.