More effective dithiocarbamate derivatives inhibiting carbonic anhydrases, generated by QSAR and computational design

被引:20
作者
Avram, Speranta [1 ]
Milac, Adina Luminita [2 ]
Carta, Fabrizio [3 ]
Supuran, Claudiu T. [3 ,4 ]
机构
[1] Univ Bucharest, Fac Biol, Dept Anat Anim Physiol & Biophys, Bucharest, Romania
[2] Romanian Acad, Inst Biochem, Bucharest 060031, Romania
[3] Univ Florence, Lab Chim Bioinorgan, Florence, Italy
[4] Univ Florence, Dipartimento Sci Farmaceut, I-50121 Florence, Italy
关键词
Tumorigenesis; antitumoral; drug design; molecular descriptor; statistical analysis; QUANTITATIVE STRUCTURE; PREDICTION;
D O I
10.3109/14756366.2012.727410
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Dithiocarbamates (DTC) are promising compounds with potential applications in antitumoral and glaucoma therapy. Our aim is to understand molecular features affecting DTC interaction with carbonic anhydrases (CAs), zinc-containing enzymes maintaining acid-base balance in blood and other tissues. To this end, we generate QSAR models based on a compound series containing 25 DTC, inhibitors of four human (h) CAs isoforms: hCA I, II, IX and XII. We establish that critical physicochemical parameters for DTC inhibitory activity are: hydrophobic, electronic, steric, topological and shape. The predictive power of our QSAR models is indicated by significant values of statistical coefficients: cross-validated correlation q(2) (0.55-0.73), fitted correlation r(2) (0.75-0.84) and standard error of prediction (0.47-0.23). Based on the established QSAR equations, we analyse 22 new DTC derivatives and identify DTC dicarboxilic acids derivatives and their esters as potentially improved inhibitors of CA I, II, IX and XII.
引用
收藏
页码:350 / 359
页数:10
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