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. 2019 Feb;59(1-2):52-59.
doi: 10.1002/ijch.201800113. Epub 2018 Oct 30.

A Chemical Biology View of Bioactive Small Molecules and a Binder-Based Approach to Connect Biology to Precision Medicines

Stuart L Schreiber  1
Affiliations

A Chemical Biology View of Bioactive Small Molecules and a Binder-Based Approach to Connect Biology to Precision Medicines

Stuart L Schreiber. Isr J Chem. 2019 Feb.
No abstract available

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Figures

Figure 1
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.
Figure 2
Figure 2
Analyses of human variants of three genes associated with risk of cardiovascular disease and altered levels of cholesterol support what we now know to be true – drugs that mimic the protective variants lower LDL levels and are heart protective. Related prospective analyses in many diseases are suggesting the activities that safe and effective drugs should confer on novel targets in the context of human physiology and prior to the start of a drug-discovery effort, but these activities are often unfamiliar to traditional efforts and may require new approaches to drug discovery. (Adapted from Reference 1.)
Figure 3
Figure 3
FKBP12 and mTOR do not associate with each other, and rapamycin does not bind mTOR – the mechanistic target of rapamycin. Rapamycin binds FKBP12 (blue) with extremely high affinity (200 pM) and the resulting small molecule-protein complex binds mTOR with high affinity and specificity (the FKBP12-rapamycin binding domain of mTOR (red) is shown). This illustrates how a small molecule can induce neo-protein associations.
Figure 4
Figure 4
Conceptual outline of a chemical biology view of bioactive small molecules. Small-molecule binding alters the dynamic properties of proteins, often pre-organizing the protein for neo-protein interactions and/or reducing the entropic cost of binding. The ability of small molecules to alter protein interactomes; post-translational modifications; cellular turnover rates and lifetimes (e. g., erlotinib, which functions as a degrader of its target EGFR); trafficking to the functionally relevant cellular compartment (e. g., tezacaftor, which functions as a translocator of its target CFTR); among others lead to the modulation of activities relevant to drug discovery. This suggests a path to drug discovery beginning with the discovery of binders followed by the systematic determination of the cellular consequences of binding.
Figure 5
Figure 5
Synthetic organic chemists are innovating methods to enable modern methods of asymmetric synthesis and strategies for short syntheses of compounds having chemical features of natural products and successful probes and drugs (eight representatives shown) to be compatible with concurrent DNA-bar coding.
See this image and copyright information in PMC

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