髓细胞白血病因子-1抑制剂的三维定量构效关系研究
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摘要
髓细胞白血病因子-1(Mcl-1)在多种细胞的生存与死亡中发挥着重要的作用,参与多种肿瘤的发生,已经成为新的研究热点。本文针对52个Mcl-1抑制剂2-吲哚酰基磺酰胺类化合物进行三维定量关系(3D-QSAR)研究,研究其结构与活性的关系。为此,基于分子的共同骨架叠合运用比较分子立场分析(CoMFA)和比较分子相似性指数分析(CoMSIA)两种经典的方法进行了三维定量构效关系的研究,建立相应模型,进行分子结构和抗肿瘤活性的分析。CoMFA模型的交叉验证系数q~2为0.714,相关系数r~2为0.992,预测相关系数r~2pred为0.654,立体场和静电场对活性的贡献为62%和38%。CoMSIA模型的交叉验证系数q~2为0.785,相关系数r~2为0.984,预测相关系数r~2pred为0.763。立体场、静电场、疏水场对活性的贡献为25.1%、41.0%和33.9%。数据证明上述模型都显示出了较好的预测性,为设计新型高活性的小分子抑制剂提供了有效信息。
Myeloid leukemia factor-1 plays an important role in the survival and death of many kinds of cells,and is involved in the occurrence of many kinds of tumors.It has become a new research hotspot.In this paper,a three-dimensional quantitative relationship(3 D-QSAR)study was performed on 52 Mcl-1 inhibitor 2-decanylsulfonamide compounds to study the relationship between their structure and activity.For this purpose,three-dimensional quantitative structure-activity relationships were studied based on the common skeleton superposition of molecules using comparative molecular position analysis(CoMFA)and comparative molecular similarity index analysis(CoMSIA),and corresponding models were established for molecular structure.And analysis of anti-tumor activity.The cross validation coefficient q~2 of the CoMFA model is 0.714,the correlation coefficient r~2 is 0.992,the prediction correlation coefficient r~2pred is 0.654,and the contribution of the stereoscopic field and the electrostatic field to the activity is 62%and 38%.The cross validation coefficient q~2 of the CoMSIA model is 0.785,the correlation coefficient r~2 is 0.984,and the prediction correlation coefficient r~2pred is 0.763.The contributions of the stereo field,electrostatic field,and hydrophobic field to the activity were respectively 25.1%,41.0%,and 33.9%.The data demonstrate that the above models have shown good predictability and provided effective information for designing novel highly active small molecule inhibitors.
Myeloid leukemia factor-1 plays an important role in the survival and death of many kinds of cells,and is involved in the occurrence of many kinds of tumors.It has become a new research hotspot.In this paper,a three-dimensional quantitative relationship(3 D-QSAR)study was performed on 52 Mcl-1 inhibitor 2-decanylsulfonamide compounds to study the relationship between their structure and activity.For this purpose,three-dimensional quantitative structure-activity relationships were studied based on the common skeleton superposition of molecules using comparative molecular position analysis(CoMFA)and comparative molecular similarity index analysis(CoMSIA),and corresponding models were established for molecular structure.And analysis of anti-tumor activity.The cross validation coefficient q~2 of the CoMFA model is 0.714,the correlation coefficient r~2 is 0.992,the prediction correlation coefficient r~2pred is 0.654,and the contribution of the stereoscopic field and the electrostatic field to the activity is 62%and 38%.The cross validation coefficient q~2 of the CoMSIA model is 0.785,the correlation coefficient r~2 is 0.984,and the prediction correlation coefficient r~2pred is 0.763.The contributions of the stereo field,electrostatic field,and hydrophobic field to the activity were respectively 25.1%,41.0%,and 33.9%.The data demonstrate that the above models have shown good predictability and provided effective information for designing novel highly active small molecule inhibitors.
引文
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[16]张贝娜,武涛,宰小丽,等.吡啶类葡萄糖激酶激动剂的三维定量构效关系分析[J].化学研究与应用,2017,29(4):492-498.
[17]宰小丽,舒茂,张贝娜,等.基于3D-QSAR及分子对接的MPS1抑制剂的构效关系研究[J].化学研究与应用,2016,28(8):1092-1097.
[2]Danial N N,Korsmeyer S J.Cell death:critical control points[J].Cell,2004,116(2):205-219.
[3]Hanahan D,Weinberg R A.The hallmarks of cancer[J].Cell,2000,100(1):57-71.
[4]Adams J,Cory S.The Bcl-2 apoptotic switch in cancer development and therapy[J].Oncogene,2007,26(9):1324-1337.
[5]Delbridge A R,Strasser A.The BCL-2 protein family,BH3-mimetics and cancer therapy[J].Cell Death Differ,2015,22(7):1071-1080.
[6]Tse C,Shoemaker A R,Adickes J,et al.ABT-263:a potent and orally bioavailable Bcl-2 family inhibitor[J].Cancer Res,2008,68(9):3421-3428.
[7]Akgul C.Mcl-1 is a potential therapeutic target in multiple types of cancer[J].Cell Mol Life Sci,2009,66(8):1326-1336.
[8]Cramer R D,Patterson D E,Bunce J D.Comparative molecular field analysis(CoMFA).1.effect of shape on binding of steroids to carrier proteins[J].J Am Chem Soc,1988,110(18):5959-5967.
[9]Klebe G,Abraham U,Mietzner T.Molecular similarity in-dices in a comparative analysis(CoMSIA)of drug molecules to correlate and predict their biological activity[J].J Med Chem,1994,37(24):4130-4146.
[10]Pelz N F,Bian Z,Zhao B,et al.Discovery of 2-Indole-acylsulfonamide myeloid cell leukemia 1(Mcl-1)inhibitors using fragment-based methods[J].J Med Chem,2016,59(5):2054-2066.
[11]Ulhaq Z,Ashraf S,Almajid A M,et al.3D-QSAR studies on barbituric acid derivatives as urease inhibitors and the effect of charges on the quality of a model[J].Int J Mol Sci,2016,17(5):657-673.
[12]Guttikonda V,Raavi D,Maadwar S K,etal.Molecular insights of benzodipyrazole as CDK2 inhibitors:combined molecular docking,molecular dynamics,and 3D QSAR studies[J].J Recept Signal Transduct Res,2015,35(5):1-11.
[13]Taha M O,HabashM,Khanfar M A.The use of docking-based comparative contacts analysis to identify optimal docking conditions within glucokinase and to discover of new GK activators[J].J Comput Aid Mol Des,2014,28(5):509-547.
[14]Pirhadi S,Ghasemi J B.3D-QSARanalysisof human immunodeficiency virus entry-1 inhibitors by CoMFA and CoMSIA[J].Eur J Med Chem,2010,45(11):4897-4903.
[15]Xie A,Sivapraksam P,Doerksen RJ.3D-QSARanalysis of antimalarial farnesyltransferase inhibitors based on a 2,5-diaminobenzophenone scaffold[J].Bioorgan Med Chem,2006,14(21):7311-7323.
[16]张贝娜,武涛,宰小丽,等.吡啶类葡萄糖激酶激动剂的三维定量构效关系分析[J].化学研究与应用,2017,29(4):492-498.
[17]宰小丽,舒茂,张贝娜,等.基于3D-QSAR及分子对接的MPS1抑制剂的构效关系研究[J].化学研究与应用,2016,28(8):1092-1097.