PDBsum entry 3ml2

Lyase/lyase inhibitor

PDB id: 3ml2

Contents

Protein chain

257 a.a.

Ligands

SU0

GOL

Metals

_ZN

Waters ×185

References listed in PDB file

Key reference

• Title: Coumarinyl-Substituted sulfonamides strongly inhibit several human carbonic anhydrase isoforms: solution and crystallographic investigations.
• Authors: J.Wagner, B.S.Avvaru, A.H.Robbins, A.Scozzafava, C.T.Supuran, R.Mckenna.
• Ref.: Bioorg Med Chem Lett, 2010, 18, 4873-4878.
• PubMed id: 20598552

Abstract

We investigated a series of coumarinyl-substituted aromatic sulfonamides as inhibitors of four carbonic anhydrase (CA, EC 4.2.1.1) isoforms with medical applications, the cytosolic hCA I, and II, and the transmembrane, tumor-associated hCA IX and XII. Compounds incorporating 7-methoxy-coumarin-4-yl-acetamide-tails and benzenesulfonamide and benzene-1,3-disulfonamide scaffolds showed medium potency inhibition of hCA I (K(I)s of 73-131nM), effective hCA II inhibition (K(I)s of 9.1-36nM) and less effective hCA IX and XII inhibition (K(I)s of 55-128nM). Only one compound, the derivatized 4-amino-6-trifluoromethyl-benzene-1,3-disulfonamide with the coumarinyl tail, showed effective inhibition of the transmembrane isoforms, with K(I)s of 5.9-14.2nM, although it was less effective as hCA I and II inhibitor (K(I)s of 36-120nM). An X-ray crystal structure of hCA II in complex with 4-(7-methoxy-coumarin-4-yl-acetamido)-benzenesulfonamide (K(I) of 9.1nM against hCA II) showed the intact inhibitor coordinated to the zinc ion from the enzyme active site by the sulfonamide moiety, and participating in a edge-to-face stacking with Phe131, in addition to other hydrophobic and hydrophilic interactions with water molecules and amino acid residues from the active site. Thus, sulfonamides incorporating coumarin rings have a distinct inhibition mechanism compared to the coumarins, and may lead to compounds with interesting inhibition profiles against various alpha-CAs found in mammals or parasites, such as Plasmodium falciparum.