Exploring benzoxaborole derivatives as carbonic anhydrase inhibitors: a structural and computational analysis reveals their conformational variability as a tool to increase enzyme selectivity

Journal of Enzyme Inhibition and Medicinal Chemistry

Jean-Yves Winum¹  Roberta Cadoni²  Anna Di Fiore³  Emma Langella³  Katia D’Ambrosio³  Vincenzo Alterio³  Giuseppina De Simone³  Simona Maria Monti³  Claudiu T. Supuran⁴ 

[1] Institut des Biomolécules Max Mousseron (IBMM) UMR 5247 CNRS, ENSCM, Université de Montpellier, Ecole Nationale Supérieure de Chimie de Montpellier, Montpellier, France;Institut des Biomolécules Max Mousseron (IBMM) UMR 5247 CNRS, ENSCM, Université de Montpellier, Ecole Nationale Supérieure de Chimie de Montpellier, Montpellier, France;Dipartimento di Chimica e Farmacia, Università Degli Studi di Sassari, Sassari, Italy;Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, Naples, Italy;Neurofarba Department, Section of Pharmaceutical and Nutriceutical Sciences, Università Degli Studi di Firenze, Florence, Ital;

关键词: Carbonic anhydrase inhibitors;    benzoxaborole derivatives;    X-ray crystallography;    binding free energy calculations;    structure-based drug design;   

DOI  :  10.1080/14756366.2019.1653291

来源: publisher

【 摘 要 】

Recent studies identified the benzoxaborole moiety as a new zinc-binding group able to interact with carbonic anhydrase (CA) active site. Here, we report a structural analysis of benzoxaboroles containing urea/thiourea groups, showing that these molecules are very versatile since they can bind the enzyme assuming different binding conformations and coordination geometries of the catalytic zinc ion. In addition, theoretical calculations of binding free energy were performed highlighting the key role of specific residues for protein-inhibitor recognition. Overall, these data are very useful for the development of new inhibitors with higher selectivity and efficacy for various CAs.

【 授权许可】

CC BY