Fat or flat? The impact of dipole moment vectors on non-covalent interactions between aromatic tags and macromolecules
The <i>closo</i>-1,2-C<sub>2</sub>B<sub>10</sub>H<sub>12</sub> carborane is a recognized 3D aromatic icosahedral building block, with an electron distribution governed by the outer hydridic BH and acidic CH vertices. We attached the carborane cage to a peptidomimetic scaffold to generate an active-site inhibitor of SmCB1, a protease drug target in the Schistosoma pathogen. The carborane-tagged compound exhibited superior inhibitor affinity and bioactivity compared to its conventional 2D aromatic phenyl analog. Quantum mechanical computations, based on the crystal structure of the protease-inhibitor complex, revealed that the carborane tag contributed to inhibitor binding not only through nonpolar interactions but also <i>via</i> a key hydrogen bond between its CH vertex and a negatively charged residue in the binding site. This interaction, driven by the large dipole moment of the carborane cage, resulted in a more favorable energy contribution than that of the phenyl group in the 2D analog. The carborane pharmacophore boosted affinity for SmCB1 and conferred specific anti-schistosomal activity, highlighting its potential in protein ligand design.
Authors
- Lorenzo Cianni
- Fernanda dos Reis Rocho (ORCID: https://orcid.org/0000-0001-8065-2532)
- Michael A. Mares (ORCID: https://orcid.org/0000-0002-0847-5022)
- Marta Chanová (ORCID: https://orcid.org/0000-0003-2191-842X)
- Conor R. Caffrey (ORCID: https://orcid.org/0000-0003-3048-8572)
- Carina Lemke
- J. Brynda (ORCID: https://orcid.org/0000-0003-3675-6769)
- Nelly El‐Sakkary (ORCID: https://orcid.org/0000-0003-3357-0424)
- Helena Mertlíková‐Kaiserová (ORCID: https://orcid.org/0000-0002-2109-4400)
- Christian Breuer (ORCID: https://orcid.org/0000-0002-3899-0631)
- Adéla Jílková (ORCID: https://orcid.org/0000-0002-3158-9626)
- Michael Gütschow (ORCID: https://orcid.org/0000-0002-9376-7897)
- Carlos Alberto Montanari (ORCID: https://orcid.org/0000-0002-4963-0316)
- Jindřich Fanfrlík (ORCID: https://orcid.org/0000-0002-1257-1201)
- Dráhomír Hnyk (ORCID: https://orcid.org/0000-0001-8094-7509)
- Martin Horn (ORCID: https://orcid.org/0000-0001-9110-2018)
- Adrian Leontovyč
- Petra Spiwoková (ORCID: https://orcid.org/0000-0002-4734-0390)
- Josef Holub (ORCID: https://orcid.org/0000-0002-8750-7933)
Institutions
- University of Bonn (DE)
- Universidade de São Paulo (BR)
- Charles University (CZ)
- Czech Academy of Sciences, Institute of Inorganic Chemistry (CZ)
- Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry (CZ)
- General University Hospital in Prague (CZ)
- University of Montana (US)
Publication Details
- Journal
- Inorganic Chemistry Frontiers
- Published
- 2025-10-21
- DOI
- https://doi.org/10.1039/d5qi01546d
- Primary Topic
- Boron Compounds in Chemistry
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- Grantová Agentura České Republiky
- Ministerstvo Zdravotnictví Ceské Republiky
- National Institutes of Health
- Helmholtz-Zentrum Berlin für Materialien und Energie