PDBsum entry 4rfc

Lyase

PDB id: 4rfc

Contents

Protein chain

257 a.a.

Ligands

3O1

Metals

_ZN

Waters ×50

References listed in PDB file

Key reference

• Title: A class of 4-Sulfamoylphenyl-ω-Aminoalkyl ethers with effective carbonic anhydrase inhibitory action and antiglaucoma effects.
• Authors: M.Bozdag, M.Pinard, F.Carta, E.Masini, A.Scozzafava, R.Mckenna, C.T.Supuran.
• Ref.: J Med Chem, 2014, 57, 9673-9686. [DOI no: 10.1021/jm501497m]
• PubMed id: 25358036

Abstract

We report a series of 4-sulfamoylphenyl-ω-aminoalkyl ethers as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The structure-activity relationship was drawn for the inhibition of four physiologically relevant isoforms: hCA I, II, IX, and XII. Many of these compounds were highly effective, low nanomolar inhibitors of all CA isoforms, whereas several isoform-selective were also identified. X-ray crystal structures of two new sulfonamides bound to the physiologically dominant CA II isoform showed the tails of these derivatives bound within the hydrophobic half of the enzyme active site through van der Waals contacts with Val135, Leu198, Leu204, Trp209, Pro201, and Pro202 amino acids. One of the highly water-soluble compound (as trifluoroacetate salt) showed effective IOP lowering properties in an animal model of glaucoma. Several fluorescent sulfonamides incorporating either the fluorescein-thiourea (7a-c) or tetramethylrhodamine-thiourea (9a,b) moieties were also obtained and showed interesting CA inhibitory properties for the tumor-associated isoforms CA IX and XII.