Fidan İsmail, Salmas Ramin Ekhteiari, Arslan Mehmet, Şentürk Murat, Durdagi Serdar, Ekinci Deniz, Şentürk Esra, Coşgun Sedat, Supuran Claudiu T
Gebze Technical University, Chemistry Department, 41400 Gebze, Kocaeli, Turkey.
Bahcesehir University, Medicinal Faculty, Department of Biophysics, 34349 Istanbul, Turkey.
Bioorg Med Chem. 2015 Dec 1;23(23):7353-8. doi: 10.1016/j.bmc.2015.10.009. Epub 2015 Oct 23.
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.
研究了一些新型甘氨酸和苯丙氨酸磺酰胺衍生物对两种人胞质碳酸酐酶同工酶I和II的抑制作用。新合成的化合物G1 - 4和P1 - 4显示出有效的抑制谱，对hCA I的KI值在14.66 - 315μM范围内，对hCA II的KI值分别在18.31 - 143.8μM范围内。为了研究这些抑制剂的结合机制，进行了计算机对接研究。对对接构象进行了原子分子动力学模拟，以说明所用抑制剂对CAII活性位点的抑制机制。这些含磺酰胺的化合物通常是以4 - 硝基苯乙酸为底物的竞争性抑制剂。这里研究的一些化合物显示出有效的hCA II抑制作用，与临床使用的磺酰胺、磺胺或甲磺灭脓在相同范围内，可能用作先导物来生成可能靶向其他尚未检测其与此类药物相互作用的CA同工酶的酶抑制剂。
