具吲哚環的抗微管蛋白化合物之三維定量構效關係研究-比較分子場分析計算

A 3D-QSAR Study of Anti-tubulin Agents with Indole Ring Using CoMFA Method

林奕宏

指導教授 ： 孫英傑

國立臺灣師範大學/理學院/化學系/碩士(2007年)

摘要

本論文以??(indole)為核心之微管蛋白聚合抑制劑進行比較分子場分析法(CoMFA)之三維定量構效關係(3S-QSAR)研究。以細胞實驗所得IC50作為活性資料，以Gold進行docking計算取得化合物構形。將42個化合物作為training set計算，得到交叉驗證相關度(q2)為0.62，以此模型預測包含17個化合物之test set，得到預測相關度(r2)為0.71，足以證明此模型深具可信度。此計算模型可以提供三度空間資訊(見下圖)，R3取代位置適合立體阻礙較大取代基；R1、R2與R4位置不適合立體阻礙大之取代基；R5與R6取代位置，部份空間呈現適合立體阻礙大取代基，部分空間則否。關於電荷作用力，R3取代位置適合偏負電荷取代基，R2取代位置有部份空間適合偏負電荷取代基，而部份空間適合偏正電荷取代基，R5取代位置適合偏正電荷，R4取代位置適合偏負電荷，R1與R6無明顯適合電性。關於模型與生物活性(IC50)被討論與分析。依據模型設計兩化合物，預測生物活性(IC50)最高提高10倍。此結果有助於發展以微管蛋白為目標之抗有絲分裂藥物。

關鍵字

微管蛋白 ； 抗微管蛋白 ； 三維定量構效關係 ； 比較分子場分析 ； 抗癌

並列摘要

A 3D-QSAR study of anti-tubulin agents with indole as nucleus core using the comparative molecular field analysis (CoMFA) was carried out. The structures of the compounds were obtained using docking calculation. CoMFA calculations for examined 42 ligands as the training set gave q2 value of 0.6 in correlation with IC50 values. Calculation for the test set of 18 ligands results in an r2 value of 0.7. The calculated results suggest that the R3 functional group site (see the below figure) favors bulky groups while R1, R2, and R4 disfavor. At the R5 and R6 sites, parts of the region favor bulky groups while other region disfavors. In the electrostatic aspect, the R3 site was found to favor groups with negative partial charges. At the R2 site, part of region favors groups with negative partial charges while other region favors groups with positive partial charges. At the R4 and R5 sites, they favor groups with negative and positive partial charges, respectively, with less favor magnitude compared with R2 and R3 sites. The R1 and R6 sites do not exhibit significant electrostatic favor. Correlation of the results with IC50 values of ligands were analyzed and discussed. These results should be of aid in developing better anti-tubulin agents of this kind.

並列關鍵字

tubulin ； anti-tubulin ； QSAR ； CoMFA ； anti-cancer

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