Carbonic anhydrase inhibitors: Design, synthesis, kinetic, docking and molecular dynamics analysis of novel glycine and phenylalanine sulfonamide derivatives

İsmail Fidan; Ramin Ekhteiari Salmas; Mehmet Arslan; Murat Şentürk; Serdar Durdagi; Deniz Ekinci; Esra Şentürk; Sedat Coşgun; Claudiu T Supuran

doi:10.1016/j.bmc.2015.10.009

Carbonic anhydrase inhibitors: Design, synthesis, kinetic, docking and molecular dynamics analysis of novel glycine and phenylalanine sulfonamide derivatives

Bioorg Med Chem. 2015 Dec 1;23(23):7353-8. doi: 10.1016/j.bmc.2015.10.009. Epub 2015 Oct 23.

Authors

İsmail Fidan¹, Ramin Ekhteiari Salmas², Mehmet Arslan³, Murat Şentürk⁴, Serdar Durdagi², Deniz Ekinci⁵, Esra Şentürk⁶, Sedat Coşgun⁷, Claudiu T Supuran⁸

Affiliations

¹ Gebze Technical University, Chemistry Department, 41400 Gebze, Kocaeli, Turkey.
² Bahcesehir University, Medicinal Faculty, Department of Biophysics, 34349 Istanbul, Turkey.
³ Yalova University, Engineering Faculty, Department of Polymer Engineering, 77100 Yalova, Turkey.
⁴ Ağrı İbrahim Çeçen University, Science and Art Faculty, Chemistry Department, 04100 Ağrı, Turkey. Electronic address: senturkm@gmail.com.
⁵ Ondokuz Mayıs University, Faculty of Agriculture, Department of Agricultural Biotechnology, 55139 Samsun, Turkey.
⁶ Ağrı İbrahim Çeçen University, School of Health Services, 04100 Ağrı, Turkey.
⁷ Fatih University, Science and Art Faculty, Chemistry Department, 34500 Istanbul, Turkey.
⁸ University of Florence, Neurofarba Department, Via Ugo Schiff 6, Polo Scientifico, 50019 Sesto Fiorentino (Firenze), Italy. Electronic address: claudiu.supuran@unifi.it.

PMID: 26534780
DOI: 10.1016/j.bmc.2015.10.009

Abstract

The inhibition of two human cytosolic carbonic anhydrase isozymes I and II, with some novel glycine and phenylalanine sulfonamide derivatives were investigated. Newly synthesized compounds G1-4 and P1-4 showed effective inhibition profiles with KI values in the range of 14.66-315μM for hCA I and of 18.31-143.8μM against hCA II, respectively. In order to investigate the binding mechanisms of these inhibitors, in silico docking studies were applied. Atomistic molecular dynamic simulations were performed for docking poses which utilize to illustrate the inhibition mechanism of used inhibitors into active site of CAII. These sulfonamide containing compounds generally were competitive inhibitors with 4-nitrophenylacetate as substrate. Some investigated compounds here showed effective hCA II inhibitory effects, in the same range as the clinically used sulfonamide, sulfanilamide or mafenide and might be used as leads for generating enzyme inhibitors possibly targeting other CA isoforms which have not been yet assayed for their interactions with such agents.

Keywords: Carbonic anhydrase; Docking; Enzyme inhibitor; Glycine; Phenylalanine; Sulfonamide.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carbonic Anhydrase I / antagonists & inhibitors
Carbonic Anhydrase I / isolation & purification
Carbonic Anhydrase II / antagonists & inhibitors
Carbonic Anhydrase II / isolation & purification
Carbonic Anhydrase Inhibitors / chemical synthesis*
Carbonic Anhydrase Inhibitors / chemistry
Enzyme Assays
Erythrocytes
Glycine / analogs & derivatives*
Glycine / chemical synthesis
Glycine / chemistry*
Humans
Models, Molecular
Molecular Docking Simulation
Molecular Dynamics Simulation
Phenylacetates / chemistry
Phenylalanine / analogs & derivatives*
Phenylalanine / chemical synthesis
Phenylalanine / chemistry*
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry*

Substances

Carbonic Anhydrase Inhibitors
Phenylacetates
Sulfonamides
Phenylalanine
Carbonic Anhydrase I
Carbonic Anhydrase II
4-nitrophenylacetic acid
Glycine