Structure–Activity Relationships of Benzenesulfonamide‐Based Inhibitors towards Carbonic Anhydrase Isoform Specificity

Abstract

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.

Carbonic Anhydrase from Porphyromonas Gingivalis as a Drug Target

“…The α-, β-, δ-, η- and, perhaps θ-CAs use as a catalytic metal the Zn(II) ion. γ-CAs are Fe(II) enzymes, but they are active also with bound Zn(II) or Co(II) ions [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ], while ζ-CAs bind Cd(II) or Zn(II) within the active site and are defined as cambialistic enzymes [ 44 , 45 , 46 ]. The metal ion from the CA active site is coordinated by three His residues in the α-, γ-, δ- and probably the θ-classes; it is coordinated by one His and two Cys residues in β- and ζ-CAs; or by two His and one Gln residues in the η-class, with the fourth ligand being a water molecule/hydroxide ion acting as a nucleophile in the catalytic cycle of the enzyme [ 10 , 13 , 15 , 47 , 48 , 49 , 50 ].…”

The Effects of Oxytocin and Oxytocin Receptor Antagonist Atosiban on the Carbonic Anhydrase and Acetylcholinesterase Enzymes from Lung Tissues of Rats

“…4.2.1.1) is a metalloenzyme that is very important for biological systems and contains a zinc (Zn + 2 ) ion in its active site [4][5][6][7]. Carbonic anhydrase is a very important enzyme, which basically ensures that the CO 2 emerging from respiration is dissolved in water, transported and driven out of body as well as plays an important role in many physiological events such as acidbase balance, ion exchange, regulation of the cardiovascular system [8,9]. The enzyme that is initially isolated from human erythrocytes has been studied via many living organisms and tissues [4].…”

Investigation of Inhibition Effect of Oxytocin on Carbonic Anhydrase and Acetylcholinesterase Enzymes in the Heart Tissues of Rats

“…- (Gulçin et al, 2004;Berg et al, 2014;Gocer et al, 2016;Kocyigit et al, 2016;Kucukoglu et al, 2016;Bhatt et al, 2017;Gul et al, 2017).…”