Si-yan Liao, Ti-fang Miao, Jin-can Chen, Hai-liang Lu, Kang-cheng Zheng. Molecular Modeling and Design of Arylthioindole Derivatives as Tubulin Inhibitors[J]. Chinese Journal of Chemical Physics , 2009, 22(5): 473-480. doi: 10.1088/1674-0068/22/05/473-480
Citation: Si-yan Liao, Ti-fang Miao, Jin-can Chen, Hai-liang Lu, Kang-cheng Zheng. Molecular Modeling and Design of Arylthioindole Derivatives as Tubulin Inhibitors[J]. Chinese Journal of Chemical Physics , 2009, 22(5): 473-480. doi: 10.1088/1674-0068/22/05/473-480

Molecular Modeling and Design of Arylthioindole Derivatives as Tubulin Inhibitors

doi: 10.1088/1674-0068/22/05/473-480
Funds:  This work was supported by the National Natural Sci-ence Foundation of China(No.20673148).We heartily thank the Molecular Discovery Ltd.for giving us the Dock 6.0 program as a freeware and the College of Life Sciences,Sun Yat-Sen University for the SYBYL 6.9 computation environment support.
  • Received Date: 2009-03-15
  • Three-dimensional quantitative structure activity relationship (3D-QSAR) and docking stud-ies of a series of arylthioindole derivatives as tubulin inhibitors against human breast cancer cell line MCF-7 have been carried out. An optimal 3D-QSAR model from the compar-ative molecular field analysis (CoMFA) for training set with significant statistical quality (R2=0.898) and predictive ability (q2=0.654) was established.The same model was further applied to predict pIC50 values of the compounds in test set,and the resulting predictive correlation coefficient R2(pred) reaches 0.816,further showing that this CoMFA model has high predictive ability. Moreover, the appropriate binding orientations and conformations of these compounds interacting with tubulin are located by docking study, and it is very in-teresting to find the consistency between the CoMFA field distribution and the 3D topology structure of active site of tubulin. Based on CoMFA along with docking results, some impor-tant factors improving the activities of these compounds were discussed in detail and were summarized as follows: the substituents R3-R5 (on the phenyl ring) with higher electroneg-ativity, the substituent R6 with higher electropositivity and bigger bulk, the substituent R7 with smaller bulk, and so on. In addition, five new compounds with higher activities have been designed. Such results can offer useful theoretical references for experimental works.
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Molecular Modeling and Design of Arylthioindole Derivatives as Tubulin Inhibitors

doi: 10.1088/1674-0068/22/05/473-480
Funds:  This work was supported by the National Natural Sci-ence Foundation of China(No.20673148).We heartily thank the Molecular Discovery Ltd.for giving us the Dock 6.0 program as a freeware and the College of Life Sciences,Sun Yat-Sen University for the SYBYL 6.9 computation environment support.

Abstract: Three-dimensional quantitative structure activity relationship (3D-QSAR) and docking stud-ies of a series of arylthioindole derivatives as tubulin inhibitors against human breast cancer cell line MCF-7 have been carried out. An optimal 3D-QSAR model from the compar-ative molecular field analysis (CoMFA) for training set with significant statistical quality (R2=0.898) and predictive ability (q2=0.654) was established.The same model was further applied to predict pIC50 values of the compounds in test set,and the resulting predictive correlation coefficient R2(pred) reaches 0.816,further showing that this CoMFA model has high predictive ability. Moreover, the appropriate binding orientations and conformations of these compounds interacting with tubulin are located by docking study, and it is very in-teresting to find the consistency between the CoMFA field distribution and the 3D topology structure of active site of tubulin. Based on CoMFA along with docking results, some impor-tant factors improving the activities of these compounds were discussed in detail and were summarized as follows: the substituents R3-R5 (on the phenyl ring) with higher electroneg-ativity, the substituent R6 with higher electropositivity and bigger bulk, the substituent R7 with smaller bulk, and so on. In addition, five new compounds with higher activities have been designed. Such results can offer useful theoretical references for experimental works.

Si-yan Liao, Ti-fang Miao, Jin-can Chen, Hai-liang Lu, Kang-cheng Zheng. Molecular Modeling and Design of Arylthioindole Derivatives as Tubulin Inhibitors[J]. Chinese Journal of Chemical Physics , 2009, 22(5): 473-480. doi: 10.1088/1674-0068/22/05/473-480
Citation: Si-yan Liao, Ti-fang Miao, Jin-can Chen, Hai-liang Lu, Kang-cheng Zheng. Molecular Modeling and Design of Arylthioindole Derivatives as Tubulin Inhibitors[J]. Chinese Journal of Chemical Physics , 2009, 22(5): 473-480. doi: 10.1088/1674-0068/22/05/473-480

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