Carbonic anhydrase inhibitors: X-ray crystallographic studies for the binding of 5-amino-1,3,4-thiadiazole-2-sulfonamide and 5-(4-amino-3-chloro-5-fluorophenylsulfonamido)-1,3,4-thiadiazole-2-sulfonamide to human isoform II

Thermodynamic, kinetic, and structural parameterization of human carbonic anhydrase interactions toward enhanced inhibitor design

“…The linker between sulfonamide group and thiadiazole ring can influence the binding mode of the inhibitor in CA II as was demonstrated in several studies (Fisher et al ., 2006; Temperini et al ., 2008 a ). Two crystal structures of CA II complexed with thiadiazolesulfonamide with halogenated benzene tail were compared (Menchise et al ., 2006). One of them was found in the structure lacking any substituent, probably due to the hydrolysis.…”

Multiple Binding Modes of Inhibitors to Carbonic Anhydrases: How to Design Specific Drugs Targeting 15 Different Isoforms?

“…118,202,207 These compounds generally retained the excellent inhibitory properties of the lead compound, but at the same time possessed much higher solubility both in water and in organic solvents, as well as better penetrability through biological membranes. 197 Several structural studies on the complexes that these heterocyclic bis-sulfonamides form with hCA II are so far available. Such studies have shown that the second sulfonamide group can help to improve the binding affinity, establishing several direct or solvent-mediated polar interactions with active site residues.…”

A Structure‐Based Virtual Screening Approach toward the Discovery of Histone Deacetylase Inhibitors: Identification of Promising Zinc‐Chelating Groups

“…In the docking simulation of 1, the central nitrogen atom of the N- [1,3,4]thiadiazol-2-yl sulfonamide moiety was assumed to be deprotonated because the acidity of the sulfonamide proton adjacent to thiadiazole or thiazole rings had been known to be strong, with an associated pK a value of~3.4. [37] In the calculated structure of the HDAC1-1 complex, we note that the nitrogen atom on the thiadiazole ring and one of the two oxygen atoms of the sulfonamide group are coordinated to the zinc ion in the active site. This pattern for the coordination of the zinc ion has not been observed elsewhere in the inhibition of HDAC so far.…”

“…We note that compounds 5 and 6 contain the hydroxamic acid moiety that serves as the zinc-chelating group in the majority of the [a] Values in parentheses indicate the atomic charges before the formation of a metal complex; see Figure 1 for the identification of the atoms. [37] Therefore, both inhibitor scaffolds warrant further development as potential anticancer drugs through structure-activity relationship (SAR) studies to improve the inhibitory activities against HDACs.…”