Chameleon (molecular)

In the field of molecular science, a chameleon molecule refers to a compound, often large and flexible, capable of dynamically altering its conformation and surface properties in response to changing environments. This unique ability, known as chameleonicity, allows such molecules to present polar surfaces in water to enhance solubility or to fold and hide these polar groups to become more cell membrane permeable in nonpolar settings. Chameleon molecules are especially significant in medicinal chemistry, where they enable the design of drugs that overcome traditional limitations in absorption and bioavailability by adapting their shape and polarity to traverse diverse biological barriers.[1]

Examples of molecules that display chameleonicity include cyclic peptides such as cyclosporine[2][3] and PROTACs such as bavdegalutamide and vepdegestrant.[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. ^ 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.
  5. ^ 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.


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