基于XED力场的碳酸酐酶Ⅸ抑制剂定量构效关系研究
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摘要
目的研究碳酸酐酶Ⅸ抑制剂的定量构效关系。方法通过分子对接方法初步确定碳酸酐酶Ⅸ抑制剂在活性口袋的结合方式,然后以化合物3b为参考分子,利用XED力场将系列化合物叠合,再构建定量构效关系模型并预测训练集化合物的活性。结果与结论分析结果显示,碳酸酐酶Ⅸ抑制剂的结合方式与理论预期相符,定量构效关系模型的r~2值为0.997,对化合物活性具有很好的预测能力,可以用来指导新型碳酸酐酶Ⅸ抑制剂的设计。
The quantitative structure-activity relationship(QSAR) of a series of novel carbonic anhydrase Ⅸ inhibitors was investigated based on the unconventional XED force field.The binding mode of carbonic anhydrase Ⅸ inhibitors were studied by molecular docking method at the active site.Taking compound 3 b as the reference molecule,a series of its analogs were superimposed to it.Then a QSAR model was built and the activities of the compounds were predicted in the training set.Through the analysis,the binding mode of carbonic anhydrase Ⅸ inhibitors was consistent with the previous study.The QSAR model has an r~2 value of 0.997,showing fairly good ability to predict the activities of compounds.Such a QSAR model is expected to be useful to help design novel carbonic anhydrase Ⅸ inhibitors in the future.
The quantitative structure-activity relationship(QSAR) of a series of novel carbonic anhydrase Ⅸ inhibitors was investigated based on the unconventional XED force field.The binding mode of carbonic anhydrase Ⅸ inhibitors were studied by molecular docking method at the active site.Taking compound 3 b as the reference molecule,a series of its analogs were superimposed to it.Then a QSAR model was built and the activities of the compounds were predicted in the training set.Through the analysis,the binding mode of carbonic anhydrase Ⅸ inhibitors was consistent with the previous study.The QSAR model has an r~2 value of 0.997,showing fairly good ability to predict the activities of compounds.Such a QSAR model is expected to be useful to help design novel carbonic anhydrase Ⅸ inhibitors in the future.
引文
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[2] SUPURAN C T,SCOZZAFAVA A.Carbonic anhydrases as targets for medicinal chemistry[J].Bioorg Med Chem,2007,15(13):4336-4350.
[3] SMEULDERS M J,BARENDS T R,POL A,et al.Evolution of a new enzyme for carbon disulphide conversion by an acidothermophilic archaeon[J].Nature,2011,478(7369):412-416.
[4] OGAWA T,NOGUCHI K,SAITO M,et al.Carbonyl sulfide hydrolase from Thiobacillus thioparus strain THI115 is one of the β-carbonic anhydrase family enzymes[J].J Am Chem Soc,2013,135(10):3818-3825.
[5] KRALL N,PRETTO F,DECURTINS W,et al.A small-molecule drug conjugate for the treatment of carbonic anhydrase Ⅸ expressing tumors[J].Angew Chem(Int Ed Engl),2014,53(16):4231-4235.
[6] CHICHE J,LAFERRIERE J,TROTTIER E,et al.Hypoxia-inducible carbonic anhydrase Ⅸ and Ⅻ promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH[J].Cancer Res,2009,69(1):358-368.
[7] CHICHE J,BRAHIMI-HORN M C,POUYSSEGUR J.Membrane-bound carbonic anhydrases are key pH regulators controlling tumor growth and cell migration[J].Adv Enzyme Regul,2010,50(1):20-33.
[8] HOU Z,LIN B,BAO Y,et al.Dual-tail approach to discovery of novel carbonic anhydrase Ⅸ inhibitors by simultaneously matching the hydrophobic and hydrophilic halves of the active site[J].Eur J Med Chem,2017,132:1-10.
[9] TANPURE R P,SUPURAN C T,POULSEN S A.Carbonic anhydrase inhibitors with dual-tail moieties to match the hydrophobic and hydrophilic halves of the carbonic anhydrase active site[J].J Med Chem,2015,58(3):1494-1505.
[10] VINTER J G.Extended electron distributions applied to the molecular mechanics of some intermolecular interactions[J].J Comput Aided Mol Des,1994,8(6):653-668.
[11] NOCENTINI A,BUA S,LOMELINO C L,et al.Discovery of new sulfonamide carbonic anhydrase Ⅸ inhibitors incorporating nitrogenous bases[J].ACS Med Chem Lett,2017,8 (12):1314-1319.
[12] WOLD S,SJ?STR?MA M,ERIKSSON L.PLS-regression:a basic tool of chemometrics[J].Chemometr Intell Lab Syst,2001,58(2):109-130.
[13] De JONG S.SIMPLS:an alternative approach to partial least squares regression[J].Chemometr Intell Lab Syst,1993,18(3):251-263.
[14] GOLBRAIKH A,TROPSHA A.Beware of q2![J].J Mol Graph Model,2002,20(4):269-276.
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