Maps of Correlations Between Compound Chemical Structures and Thermodynamics of Binding to 12 Human Carbonic Anhydrases: Towards Isoform-Selective Inhibitors

In the design of target-based pharmaceutical compounds it is important to synthesize chemical compounds that would bind with high affinity to target protein and would not bind to any unintended protein. Thus, the compounds should possess high selectivity towards the target protein, a feature that is difficult to achieve because the correlations between compound structures and their affinities for the target are rather poorly understood. Here we build and analyze maps that compare between compounds of similar structures and demonstrate how small changes of compound functional groups influence their capability to bind a particular CA isoform and at the same time may improve selectivity over the remaining non-target 11 catalytically active CA isoforms. The analysis of such correlations has helped to synthesize compounds that possess picomolar affinities towards some CAs and demonstrate up to million-fold selectivities for the target isoform. In addition to the intrinsic affinities of the compounds, we have analyzed other thermodynamic parameters, the intrinsic enthalpy and entropy changes upon binding, providing information on the contacts and bonds between the compound and the protein.