Interaction Studies Between Carbonic Anhydrase and a Sulfonamide Inhibitor by Experimental and Theoretical Approaches

: The most used approaches in structure-based drug design possess peculiar characteristics with advantages and limitations, and thus the management of complementary data from various techniques is of particular interest to synergistically achieve the development of e ff ective enzyme inhibitors. In this Letter, we describe the application of experimental and computational techniques to study the interactions between human carbonic anhydrases and sulfonamide inhibitors. In particular, a series of a ffi nity-labeled carbonic anhydrase inhibitors containing sulfonamido photoprobes was designed and synthesized, and one of these compounds, a benzophenone derivative, was chosen as a model photoprobe/inhibitor. A photoa ffi nity labeling method followed by mass spectrometry analysis was then applied to elucidate the inhibitor binding site, and a comparison with X-ray crystallography and molecular dynamics simulation data was carried out, highlighting that to have a comprehensive view of the protein/inhibitor complex stabilization all three kinds of experiments are necessary.