Correlations Between Inhibitor Binding Thermodynamics and Co-crystal Structures with Carbonic Anhydrases

Abstract

In order to be able to design chemical compounds that recognize a particular CA isoform, meaning that they would bind particular isoform with high affinity while not binding other isoforms, it is important to understand how compounds recognize the protein surface. To understand which structural features yield what types of changes in the binding energetics, we search for correlations between compound–isoform co-crystal structures and intrinsic thermodynamics of binding. The compounds are being compared by arranging them in matched molecular pairs that differ by a single functional group responsible for the change in binding thermodynamics. Part of the ligands bound in similar orientations of the benzenesulfonamide ring, while others bound in dissimilar orientation. All similar binders exhibited significant increase in entropic forces upon increase in the buried surface of the compounds, while dissimilar binders had various thermodynamics. Several mechanisms were identified, perfect geometry fit and a molecular trap. The softness of the CA active site and the water molecules are also discussed.