1. Structure-Activity Relationships of Benzenesulfonamide-Based Inhibitors towards Carbonic Anhydrase Isoform Specificity
- Author
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Mariangela Ceruso, Brian P. Mahon, Adrian E. Roitberg, Avni Bhatt, Robert McKenna, Vinícius Wilian D. Cruzeiro, Benedetta Cornelio, Claudiu T. Supuran, Antonella Fontana, Graham A. Rance, Janos Sapi, Marie Laronze-Cochard, Andrei N. Khlobystov, University of Florida [Gainesville] (UF), Institut de Chimie Moléculaire de Reims - UMR 7312 (ICMR), SFR Condorcet, Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Università degli studi 'G. d'Annunzio' Chieti-Pescara [Chieti-Pescara] (Ud'A), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), School of Chemistry, The University of Nottingham, University Park, Nottingham, NG7 2RD, UK., School of Chemistry, The University of Nottingham, University Park, Nottingham, NG7 2RD, UK. Code (UMR, EA, ...), and Laboratorio di Chimica Bioinorganica (LCBI)
- Subjects
0301 basic medicine ,Gene isoform ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,Selective inhibition ,Crystallography, X-Ray ,01 natural sciences ,Biochemistry ,Structure-Activity Relationship ,03 medical and health sciences ,Downregulation and upregulation ,Catalytic Domain ,Carbonic anhydrase ,Protein Isoforms ,Carbonic Anhydrase Inhibitors ,Molecular Biology ,Carbonic Anhydrases ,Sulfonamides ,Binding Sites ,biology ,[CHIM.ORGA]Chemical Sciences/Organic chemistry ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Active site ,Ligand (biochemistry) ,Small molecule ,Affinities ,3. Good health ,0104 chemical sciences ,Molecular Docking Simulation ,030104 developmental biology ,Drug Design ,biology.protein ,Molecular Medicine ,Protein Binding - Abstract
International audience; Carbonic anhydrases (CAs) are implicated in a wide range of diseases, including the upregulation of isoforms CA IX and XII in many aggressive cancers. However, effective inhibition of disease‐implicated CAs should minimally affect the ubiquitously expressed isoforms, including CA I and II, to improve directed distribution of the inhibitors to the cancer‐associated isoforms and reduce side effects. Four benzenesulfonamide‐based inhibitors were synthesized by using the tail approach and displayed nanomolar affinities for several CA isoforms. The crystal structures of the inhibitors bound to a CA IX mimic and CA II are presented. Further in silico modeling was performed with the inhibitors docked into CA I and XII to identify residues that contributed to or hindered their binding interactions. These structural studies demonstrated that active‐site residues lining the hydrophobic pocket, especially positions 92 and 131, dictate the positional binding and affinity of inhibitors, whereas the tail groups modulate CA isoform specificity. Geometry optimizations were performed on each ligand in the crystal structures and showed that the energetic penalties of the inhibitor conformations were negligible compared to the gains from active‐site interactions. These studies further our understanding of obtaining isoform specificity when designing small molecule CA inhibitors.
- Published
- 2016