Improving binding entropy by higher ligand symmetry? - A case study with human matriptase

• Published in: MedChemComm 2023-05, Vol.14 (5), p.969-982
• Main Authors: Hammerschmidt, Stefan J, Maus, Hannah, Weldert, Annabelle C, Gütschow, Michael, Kersten, Christian
• Format: Article
• Language: English
• Subjects: Affinity; Binding sites; Calorimetry; Entropy; Ligands; Optimization; Phloroglucinol; Symmetry; Titration; Titration calorimetry
• ISSN: 2632-8682; 2040-2503; 2632-8682; 2040-2511
• DOI: 10.1039/d3md00125c

Understanding different contributions to the binding entropy of ligands is of utmost interest to better predict affinity and the thermodynamic binding profiles of protein-ligand interactions and to develop new strategies for ligand optimization. To these means, the largely neglected effects of introducing higher ligand symmetry, thereby reducing the number of energetically distinguishable binding modes on binding entropy using the human matriptase as a model system, were investigated. A set of new trivalent phloroglucinol-based inhibitors that address the roughly symmetric binding site of the enzyme was designed, synthesized, and subjected to isothermal titration calorimetry. These highly symmetric ligands that can adopt multiple indistinguishable binding modes exhibited high entropy-driven affinity in line with affinity-change predictions. Highly symmetric ligands can bind in multiple identical binding modes. The improved binding affinity arising from higher entropy was elucidated in this work.