Chameleon (molecular)

In the field of chemistry, a chameleon is a molecule that can adopt different conformations in response to being exposed to different environments.[1] In an aqueous environment, chameleon molecules expose polar hydrophilic groups. Conversely in hydrophobic environments such as the interior of cell membranes, chameleon molecules expose hydrophobic groups.

Examples of molecules with chameleon properties include cyclic peptides such as the drug cyclosporin A. This chameleon property allows the drug to dissolve in water and then traverse the hydrophobic intestinal epithelium bilayer and then dissolve in blood serum, allowing high oral bioavailability. These same properties then allow diffusion across the lipid bilayer and to achieve high intracellular concentrations in the target cells increasing the potency of these drugs.[2][3]

Chameleonicity may also contribute increased bioavailability and membrane permeability of PROTACs.[4][5]

References

  1. ↑ Poongavanam V, Wieske LH, Peintner S, Erdélyi M, Kihlberg J (January 2024). "Molecular chameleons in drug discovery". Nature Reviews. Chemistry. 8 (1): 45–60. doi:10.1038/s41570-023-00563-1. PMID 38123688.
  2. ↑ Ono S, Naylor MR, Townsend CE, Okumura C, Okada O, Lee HW, et al. (November 2021). "Cyclosporin A: Conformational Complexity and Chameleonicity". Journal of Chemical Information and Modeling. 61 (11): 5601–5613. doi:10.1021/acs.jcim.1c00771. PMC 9531541. PMID 34672629.
  3. ↑ Ramelot TA, Palmer J, Montelione GT, Bhardwaj G (June 2023). "Cell-permeable chameleonic peptides: Exploiting conformational dynamics in de novo cyclic peptide design". Current Opinion in Structural Biology. 80 102603. doi:10.1016/j.sbi.2023.102603. PMC 10923192. PMID 37178478.
  4. ↑ Apprato G, Poongavanam V, Garcia Jimenez D, Atilaw Y, Erdelyi M, Ermondi G, et al. (April 2024). "Exploring the chemical space of orally bioavailable PROTACs". Drug Discovery Today. 29 (4) 103917. doi:10.1016/j.drudis.2024.103917. PMID 38360147.
  5. ↑ Garcia Jimenez D, Vallaro M, Rossi Sebastiano M, Apprato G, D'Agostini G, Rossetti P, et al. (August 2023). "Chamelogk: A Chromatographic Chameleonicity Quantifier to Design Orally Bioavailable Beyond-Rule-of-5 Drugs". Journal of Medicinal Chemistry. 66 (15): 10681–10693. doi:10.1021/acs.jmedchem.3c00823. PMC 10424176. PMID 37490408.


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