Insights into the binding mode of sulphamates and sulphamides to hCA II: crystallographic studies and binding free energy calculations
Autor: | Giuseppina De Simone, Emma Langella, Davide Esposito, Claudiu T. Supuran, Simona Maria Monti, Jean-Yves Winum, Vincenzo Alterio |
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Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: | |
Zdroj: | Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 32, Iss 1, Pp 1002-1011 (2017) |
Druh dokumentu: | article |
ISSN: | 1475-6366 1475-6374 14756366 |
DOI: | 10.1080/14756366.2017.1349764 |
Popis: | Sulphamate and sulphamide derivatives have been largely investigated as carbonic anhydrase inhibitors (CAIs) by means of different experimental techniques. However, the structural determinants responsible for their different binding mode to the enzyme active site were not clearly defined so far. In this paper, we report the X-ray crystal structure of hCA II in complex with a sulphamate inhibitor incorporating a nitroimidazole moiety. The comparison with the structure of hCA II in complex with its sulphamide analogue revealed that the two inhibitors adopt a completely different binding mode within the hCA II active site. Starting from these results, we performed a theoretical study on sulphamate and sulphamide derivatives, demonstrating that electrostatic interactions with residues within the enzyme active site play a key role in determining their binding conformation. These findings open new perspectives in the design of effective CAIs using the sulphamate and sulphamide zinc binding groups as lead compounds. |
Databáze: | Directory of Open Access Journals |
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