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請使用永久網址來引用或連結此文件:
https://ir.csmu.edu.tw:8080/ir/handle/310902500/10329
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| 題名: | 探討新開發之AM-Mesitylglycinamide 化合物對於KCNQ 蛋白之作用機轉與其可能的應用
Study of the Novel Compound, AM-Mesitylglycinamide Acting on KCNQ and Its Possible Applications in Medicine |
| 作者: | 林明忠 |
| 貢獻者: | 生物醫學科學系 |
| 關鍵詞: | Kv7蛋白;Kv7 開啟劑;KCNQ 變異;AM-342;CH-335;BM-321;藥物篩選
Kv7 protein;Kv7 openers;KCNQ4 mutants;AM-342;CH-335;BM -321;drug screening |
| 日期: | 2014 |
| 上傳時間: | 2015-02-25T09:18:22Z (UTC)
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| 摘要: | Kv7 蛋白(KCNQ)開啟劑是近年來新發展的一群在臨床上很有潛力的神經疾病治療藥 物。因此開發新的 Kv7蛋白作用劑與探討作用劑產生作用的分子決定位對於未來的臨床應 用上具有其價值。此研究計畫分成兩個部份探討，其一是開發新的 Kv7作用劑目前我們初 步的結果已找到 3 個較強效的作用劑 AM-342 (AM-mesitylglycinamide)、CH-335 (CH-mesitylprolinamide) 與 BM -321 (BM-piperidinecarboxamide)，將進一步的探討其詳細 的機轉 (第一年)，其二是試圖探索這些新穎且有效的 Kv7開啟劑的分子決定位 (第二年)。 最初我們以ML213與 retigabine為結構藍圖，使用 ChemBridge (Hit2Lead.com)資料庫 中超過 90萬個化合物，依其結構相似度與相關物性參數篩選出約 21個可能的化合物(已存 於本實驗室中)，再從這 21 個化合物中從初步結果中找到 3 個強效的作用劑，我們將分別 探討這三種藥物的 EC50與詳細的作用機轉。 另外這 3個化合物的分子作用點方面首先我們參考之前的文獻並使用多重序列比對找 出 retigabine作用於 Kv7.4 的可能位點，其可能的位點有 5個: Trp-242, Leu-249, Leu-274, Leu-305 與 Gly-307 (皆位於 S5-loop-S6 區域)。建構這 5 個變異的質體並表達蛋白於 HEK293t細胞株中，然後觀察這 3個化合物對這 5個變異蛋白的作用是否產生改變。如果 某個Kv7.4 突變蛋白對於這 3個化合物的作用失去敏感性則該位點可能為它們產生藥物活 性的分子決定位之一。因此這個計畫的完成將可完成評估這些新開發的 Kv7作用劑並瞭解 它們的作用機轉，此外也可得知這些新開發 Kv7作用劑在蛋白上的分子決定位，進一步地 我們或可瞭解增強 Kv7開啟劑其結構上的重要基團，此可做為未來開發新藥的藍圖。
The Kv7 protein (KCNQ) openers (activators) are a new development group of potential clinical neurological disease therapy in recent years. Therefore, it is valuable to development new compounds for Kv7 opener for future clinical applications and to understand the molecular determinants of Kv7 openers (and its analogs) interact with Kv7 protein. This research project is divided into two parts to explore. One is to development new compounds acting on Kv7 protein and to investigate the action mechanism of these new compounds (the first year). In the preliminary data we have found the three new compounds (AM-342, CH-335 and BM -321) which act on Kv7 protein. The other is trying to investigate the molecular determinants of AM-342, CH-335 and BM -321 on Kv7 protein (the second year). We based on ML213 and retigabine as the molecular structure blueprint to screen 900,000 chemical compounds from ChemBridge (Hit2Lead.com). The twenty-one compounds were screened according the structure similarly and related physical properties of compounds. Furthermore the three potent compounds (AM-342, CH-335 and BM -321) are further screened. The mechanism of action and EC50 of the three novel compounds are needed to further investigation. The other is trying to understand the molecular determinants of AM-342, CH-335 and BM -321 on the Kv7 protein. We referred to previous literature for the molecular determinants of retigabine on Kv7 protein. The possible molecular determinants, Trp-242, Leu-249, Leu-274, Leu-305 and Gly-307 (all within in S5-loop-S6 region) are obtained by using the multiple sequence alignment (Clustalw 2.0) between Kv7.4 and its homologous proteins. Five human KCNQ4 mutants (W242L, L249W, L2742, L305W and G307A) were constructed using by site-directed mutagenesis and mutants are expressed in HEK293t cell line. The three novel compounds and its analogs interact with KV7.4 mutants will be observed and then to compare the activating effect of these analogs in between Kv7.4 wild-type and mutant proteins. Those mutations causing the cells to lose sensitivity to the three novel compounds can be identified a crucial amino acid important for the analogs binding on Kv7.4. Therefore, the completion of this project will be obtained the action mechanism and molecular determinants of these novel compounds on the Kv7 protein. In addition it is important that we can understand the key structure group of the increased potency of drugs. This can be as a blueprint for the future development of new drugs. |
| URI: | https://ir.csmu.edu.tw:8080/ir/handle/310902500/10329 |
| 顯示於類別: | [生物醫學科學學系暨碩士班] 研究計劃
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