Fat or flat? The impact of dipole moment vectors on non-covalent interactions between aromatic tags and macromolecules.

The closo-1,2-C2B10H12 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.