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Molecular chameleons in drug discovery

Nature Reviews Chemistry volume 8, pages 45–60 (2024)Cite this article

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Abstract

Molecular chameleons possess a flexibility that allows them to dynamically shield or expose polar functionalities in response to the properties of the environment. Although the concept of molecular chameleons was introduced already in 1970, interest in them has grown considerably since the 2010s, when drug discovery has focused to an increased extent on new chemical modalities. Such modalities include cyclic peptides, macrocycles and proteolysis-targeting chimeras, all of which reside in a chemical space far from that of traditional small-molecule drugs. Both cell permeability and aqueous solubility are required for the oral absorption of drugs. Engineering these properties, and potent target binding, into the larger new modalities is a more daunting task than for traditional small-molecule drugs. The ability of chameleons to adapt to different environments may be essential for success. In this Review, we provide both general and theoretical insights into the realm of molecular chameleons. We discuss why chameleons have come into fashion and provide a do-it-yourself toolbox for their design; we then provide a glimpse of how advanced in silico methods can support molecular chameleon design.

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Fig. 1: Illustration of how the molecular chameleon telithromycin achieves aqueous solubility, cell permeability and broad-spectrum activity.
Fig. 2: Impact of molecular chameleonicity on cell permeability and aqueous solubility.
Fig. 3: Molecular chameleons from different classes of compounds in the beyond-Ro5 space.
Fig. 4: Conformational flexibility allows chameleons to bind targets that differ in structure.
Fig. 5: Tips and tricks for the design of molecular chameleons.
Fig. 6: Computer-aided design of molecular chameleons.

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Acknowledgements

We thank A. Sheikh and R. Hong for helpful discussions on paritaprevir, and G. Bhardwaj for providing the two predicted low-energy conformations of cyclic peptide 27. The writing of this manuscript was supported by a grant from the Swedish Research Council (Grant No. 2021-04747).

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  1. Department of Chemistry – BMC, Uppsala University, Uppsala, Sweden

    Vasanthanathan Poongavanam, Lianne H. E. Wieske, Stefan Peintner, Máté Erdélyi & Jan Kihlberg

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  1. Vasanthanathan Poongavanam
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Contributions

J.K. conceptualized and wrote the manuscript, with contributions from V.P., L.H.E.W., S.P. and M.E. V.P. performed the computational analysis, searched the literature and made the submitted figures. L.H.E.W., S.P. and V.P. downloaded and curated a dataset of crystal structures from which examples were chosen to illustrate different aspects of molecular chameleonicity.

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Correspondence to Jan Kihlberg.

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Poongavanam, V., Wieske, L.H.E., Peintner, S. et al. Molecular chameleons in drug discovery. Nat Rev Chem 8, 45–60 (2024). https://doi.org/10.1038/s41570-023-00563-1

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