The antibiotic furagin and its derivatives are isoform-selective human carbonic anhydrase inhibitors

Abstract

The clinically used antibiotic Furagin and its derivatives possess inhibitory activity on human (h) carbonic anhydrases (CA, EC 4.2.1.1), some of which are highly expressed in various tissues and malignancies (hCA IX/XII). Furagin exhibited good hCA IX and XII inhibition with K I s of 260 and 57 nM, respectively. It does not inhibit off-target CA I and poorly inhibited CA II (K I ¼ 9.6 lM). Some synthesised Furagin derivatives with aminohydantoin moieties as zinc binding group exhibited weak inhibition of CA I/II, and good inhibition of CA IX/XII with K I s ranging from 350 to 7400 and 150 to 5600 nM, respectively. Docking and molecular dynamics simulations suggest that selectivity for the cancer-associated CA IX/XII over CA II is due to strong H-bond interactions in CA IX/XII, involving the tail orientated towards hydrophobic area of the active site. These results suggest a possible drug repurposing of Furagin as anti-cancer agent.

Identification of New Carbonic Anhydrase VII Inhibitors by Structure-Based Virtual Screening

“…It should be noted that, to our knowledge, there are no activity reports of nitrofurantoin against other hCA isoforms so far. Structurally related compounds such as furagin and its derivatives were recently reported to be potent inhibitors of hCA IX/XII and poor inhibitors of hCA II, but they were not studied against isoform VII …”

“…Structurally related compounds such as furagin and its derivatives were recently reported to be potent inhibitors of hCA IX/XII and poor inhibitors of hCA II, but they were not studied against isoform VII. 55 ■ CONCLUSIONS An AutoDock4 Zn -based molecular docking protocol has been developed for the search of new hCA VII inhibitors by VS. By means of the in silico validation process, optimal simulation parameters were established. The model showed a good ability to reproduce the experimental pose of the analyzed ligands, a good performance to discriminate between inhibitors and noninhibitors, and the ability to recover active structures at the top of an ordered database.…”

Novel benzenesulfonamide‐bearing pyrazoles and 1,2,4‐thiadiazoles as selective carbonic anhydrase inhibitors

“…The best pose for each compound, evaluated in terms of coordination, hydrogen‐bond interactions, and hydrophobic contacts, was redocked by Prime [ 59a ] MM‐GBSA (molecular mechanics with generalized Born and surface area) calculations using a VSGB solvation model considering the flexible target within 3 Å around the ligand, with this latter distance being considered the best compromise to achieve the most reliable binding‐free energies. [ 60–62 ]…”

Sulfonamide Inhibitors of Human Carbonic Anhydrases Designed through a Three-Tails Approach: Improving Ligand/Isoform Matching and Selectivity of Action

“…The detailed knowledge of the active site composition and architecture of hCAs (mostly available by X-ray crystallographic studies, except for CAs VA and VB) derived from many previous studies − led to the conclusion that the simple hydrophobic/hydrophilic division of the isoforms binding pocket may no longer be sufficient. In fact, some CA isozymes do not exhibit such a precise distinction as originally noted in hCA I, II, and IX, and a bulk of accessory subpockets exist, which differentiate the various CA isoforms.…”