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Publication Abstract from PubMed

The closo-1,2-C(2)B(10)H(12) 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 via 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.

Fat or flat? The impact of dipole moment vectors on non-covalent interactions between aromatic tags and macromolecules.,Holub J, Jilkova A, Lemke C, Cianni L, Spiwokova P, Horn M, Breuer C, Leontovyc A, Brynda J, Mertlikova-Kaiserova H, Chanova M, Dos Reis Rocho F, Montanari CA, El-Sakkary N, Caffrey CR, Gutschow M, Hnyk D, Mares M, Fanfrlik J Inorg Chem Front. 2025 Oct 21. doi: 10.1039/d5qi01546d. PMID:41127420^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.