Carbonic Anhydrase-Encoded Dynamic Constitutional Libraries: Toward the Discovery of Isozyme-Specific Inhibitors

Abstract

A constitutional dynamic library (CDL) was generated under thermodynamic control by using the amino-carbonyl/imine interconversion as reversible chemistry, combined with noncovalent bonding within the active site of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Considering the pharmacological importance to find isoform-selective CA inhibitors (CAIs), two of the 15 human (h) isoform, i.e., hCAI and hCA II, have been subjected to a parallel screening of the same CDL. The use of parallel constitutional screening of CDL chemistry for the discovery of enzyme inhibitors is straightforward and it might provide initial insights toward the generation of efficient classes of selective, high affinity inhibitors. We demonstrate here that the high selectivity and specificity of inhibiting the hCA I and hCA II isozymes with some of the detected hits may be used to describe a complex constitutional behavior through component selection from the dynamic library, driven by the selective binding to the specific isoform active site. These results also point to the possibility of modulating the drug discovery methods by constitutional recomposition induced by a specific enzymatic target.