Abstract
The potential utility of synthetic macrocycles (MCs) as drugs, particularly against low-druggability targets such as protein-protein interactions, has been widely discussed. There is little information, however, to guide the design of MCs for good target protein–binding activity or bioavailability. To address this knowledge gap, we analyze the binding modes of a representative set of MC–protein complexes. The results, combined with consideration of the physicochemical properties of approved macrocyclic drugs, allow us to propose specific guidelines for the design of synthetic MC libraries with structural and physicochemical features likely to favor strong binding to protein targets as well as good bioavailability. We additionally provide evidence that large, natural product–derived MCs can bind targets that are not druggable by conventional, drug-like compounds, supporting the notion that natural product–inspired synthetic MCs can expand the number of proteins that are druggable by synthetic small molecules.
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Acknowledgements
This research was supported by US National Institutes of Health grants GM094551 to A.W., S.V. and J.A.P. and GM064700 to S.V. and NIH diversity supplement GM094551-01S1 to E.A.V.
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A.W., S.V. and D.K. conceived of and directed the study; E.A.V. performed the calculations and analysis, with advice from D.B.; S.C., under the supervision of J.A.P., analyzed the physicochemical properties of the MC drugs; and A.W. and E.A.V. wrote the manuscript with input from S.V., D.K. and S.C.
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Villar, E., Beglov, D., Chennamadhavuni, S. et al. How proteins bind macrocycles. Nat Chem Biol 10, 723–731 (2014). https://doi.org/10.1038/nchembio.1584
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DOI: https://doi.org/10.1038/nchembio.1584
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