Identification of novel 5-hydroxy-1<Emphasis Type="Italic">H</Emphasis>-indole-3-carboxylates with anti-HBV activities based on 3D QSAR studies |
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Authors: | Hui-fang Chai Xin-xia Liang Lin Li Chun-shen Zhao Ping Gong Zhong-jie Liang Wei-liang Zhu Hua-liang Jiang Cheng Luo |
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Institution: | (1) Department of Pharmacy, Guiyang College of Traditional Chinese Medicine, Guiyang, 550002, China;(2) Guizhou Province Key Laboratory of Fermentation Engineering and Biological Pharmacy, Guizhou University, Guiyang, 550003, China;(3) Division of Nephrology, Shanghai Changzheng Hospital, Shanghai, 200003, China;(4) School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China;(5) Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China |
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Abstract: | Infection with hepatitis B virus (HBV) is a major cause of liver diseases such as cirrhosis and hepatocellular carcinoma.
In our previous studies, we identified indole derivatives that have anti-HBV activities. In this study, we optimize a series
of 5-hydroxy-1H-indole-3-carboxylates, which exhibited potent anti-HBV activities, using three-dimensional quantitative structure-activity
relationship (3D QSAR) studies with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices
analysis (CoMSIA). The lowest energy conformation of compound 3, which exhibited the most potent anti-HBV activity, obtained from systematic search was used as the template for alignment.
The best predictions were obtained with the CoMFA standard model (q
2 = 0.689, r
2 = 0.965, SEE = 0.082, F = 148.751) and with CoMSIA combined steric, electrostatic, hydrophobic and H-bond acceptor fields
(q
2 = 0.578, r
2 = 0.973, SEE = 0.078, F = 100.342). Both models were validated by an external test set of six compounds giving satisfactory
prediction. Based on the clues derived from CoMFA and CoMSIA models and their contour maps, another three compounds were designed
and synthesized. Pharmacological assay demonstrated that the newly synthesized compounds possessed more potent anti-HBV activities
than before (IC50: compound 35a is 3.1 μmol/l, compound 3 is 4.1 μmol/l). Combining the clues derived from the 3D QSAR studies and from further validation of the 3D QSAR models, the
activities of the newly synthesized indole derivatives were well accounted for. Furthermore, this showed that the CoMFA and
CoMSIA models proved to have good predictive ability. |
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Keywords: | |
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