Correlations between Thermodynamics and Structure of Carbonic Anhydrase-Inhibitor Binding

Abstract

The fundamental principles that determine the affinity between a protein and a small compound are not well understood. Therefore, novel pharmaceuticals are often discovered by performing laborious and expensive high-throughput random screens while the rational protein-target structure-based drug design is complicated and compound structures are difficult to be discovered in silico. We investigate a family of twelve structurally similar human proteins, carbonic anhydrases (CAs), and their inhibitors, aromatic compounds with a pharmacophoric sulfonamide group. This system is suitable both as a model for biophysical understanding of protein-small compound interactions and also a new inhibitor could have a potential to be clinically applicable. Our aim is to correlate the crystal structures with the binding thermodynamic parameters (change in standard enthalpy, entropy, and Gibbs energy upon binding) between the protein and small molecule. We have determined a number of examples where the influence of water molecules on binding, steric interference, the influence of halogen atoms of compound and other structurally distinct effects have been demonstrated. Testing of chemically similar compound binding to CAs gives an opportunity to track changes of binding affinity and selectivity. Despite the similarity between CA isoforms, we have come to understand some rules on how to design compounds with pM affinity and high selectivity for certain CA isoforms.