رسالة جامعية
Identification of the Potential Src Inhibitors against Non-small Cell Lung Cancer by 3D-QSAR Pharmacophore-based Virtual Screening and Molecular Docking
| العنوان: | Identification of the Potential Src Inhibitors against Non-small Cell Lung Cancer by 3D-QSAR Pharmacophore-based Virtual Screening and Molecular Docking |
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| العنوان البديل: | 以三維定量構效關係藥效基團為基礎之虛擬篩選與分子對接方法來鑑定可抑制非小細胞肺癌Src抑制劑 |
| المؤلفون: | Jia-Hua Li, 李佳樺 |
| مرشدي الرسالة: | Jeremy J.W. Chen, 陳健尉 |
| سنة النشر: | 2016 |
| المجموعة: | National Digital Library of Theses and Dissertations in Taiwan |
| الوصف: | 104 Target therapy is a newer type of cancer treatment that uses drugs to more precisely identify and attack cancer cells, usually while doing little damage to normal cells. Increased c-Src activity and expression are related to tumor progression, poor prognosis and metastasis of lung cancer. This study aims to develop c-Src inhibitors for the treatment of lung cancer. In this study, we have developed two types of pipelines combining 3D-QSAR pharmacophore modeling and molecular docking approach, useful for the virtual screening on the NCI anti-cancer drugs. The first pipeline uses single pharmacophore model as screening tool; moreover, the second pipeline adopts multiple pharmacophore models to perform virtual screening. We applied a series of structurally diverse compounds exhibiting IC50 value from 2 nM to 50000 nM to generate the pharmacophore model by Discovery Studio 3.5 HypoGen module. These compounds were retrieved from BindingDB Database. It was subsequently combined with pharmacophore mapping, docking score, binding energy and ten different scoring functions to select candidate compounds. In total, 30 and 39 NCI anti-cancer drugs identified from two types of virtual screening methods, respectively. Then, we used the enzyme-linked immunosorbent assay (ELISA) to identify the compounds that can inhibit Src pY419 phosphorylation more than 60%. Finally, two candidate compounds (Ph and Py) were selected to confirm the activity by western blot analysis from single pharmacophore-based screening. The results showed that Ph could inhibit Src, Stat3, FAK, Paxillin and P130cas phosphorylation, and also suppress the invasion and migration abilities in A549 lung cancer cell line. Ph also suppresses the colony formation in A549 and H358 lung cancer cell lines. Furthermore, we also used ELISA to confirm 12 compounds that could inhibit Src pY419 phosphorylation from multiple pharmacophore-based screening. In summary, we set up two different screening strategies to discovery potential c-Src inhibitors and provided the experimental results to support the inhibitory ability for c-Src of the potential inhibitors. These strategies and findings will help us to develop the drugs for treatment of non-small cell lung cancer. |
| Original Identifier: | 104NCHU5114001 |
| نوع الوثيقة: | 學位論文 ; thesis |
| وصف الملف: | 106 |
| الإتاحة: | http://ndltd.ncl.edu.tw/handle/18751842841587721177Test |
| رقم الانضمام: | edsndl.TW.104NCHU5114001 |
| قاعدة البيانات: | Networked Digital Library of Theses & Dissertations |
| الوصف غير متاح. |