Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 13, Issue 2, Pages 271-277Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.1c00644
Keywords
Carbonic anhydrase; sulfonamides; molecular recognition; photoaffinity labeling; X-ray crystallography; molecular modeling
Categories
Funding
- Sardegna Ricerche, Science and Technology Park of Sardinia
- Italian Ministry of Research and University (MIUR), grant PRIN [2017XYBP2R]
- FAR2020
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The letter describes the application of experimental and computational techniques to study the interactions between human carbonic anhydrases and sulfonamide inhibitors. A series of affinity-labeled carbonic anhydrase inhibitors containing sulfonamido photoprobes was designed and synthesized, and a photoaffinity labeling method followed by mass spectrometry analysis was applied to elucidate the inhibitor binding site. Comparisons with X-ray crystallography and molecular dynamics simulation data were made to fully understand the protein/inhibitor complex stabilization.
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 effective 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 affinity-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 photoaffinity 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.
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