本文關(guān)鍵詞： 分子設(shè)計 合成 抗凝活性 氟化 達(dá)比加群衍生物　出處：《上海應(yīng)用技術(shù)大學(xué)》2016年碩士論文　論文類型：學(xué)位論文

【摘要】：本文研究主要內(nèi)容是結(jié)合達(dá)比加群在抗凝血治療中的優(yōu)勢以及氟原子在藥物分子設(shè)計中的優(yōu)點,利用計算機(jī)輔助藥物設(shè)計軟件SYBYL-X 2.0. (Tripos Inc., St. Louis, USA)下的Surflex-Dock模塊,以凝血酶蛋白(PDB:1KTS)作為受體對達(dá)比加群的衍生物進(jìn)行計算機(jī)輔助模擬和分子對接,在直接凝血酶抑制劑達(dá)比加群中引入氟,并且對其進(jìn)行結(jié)構(gòu)修飾,設(shè)計出一系列新穎的氟化達(dá)比加群衍生物,通過對這些化合物進(jìn)行計算機(jī)模擬打分,篩選出打分值高的15個化合物,通過邁克爾加成、�；⑦�原、縮合閉環(huán)、Pinner反應(yīng)、以及水解反應(yīng)最終合成新型氟化達(dá)比加群衍生物。通過對這些化合物進(jìn)行抑制率篩選,11個衍生物被選出進(jìn)行體外抗凝血活性測試研究,測試結(jié)果表明,所有化合物具有穩(wěn)定溫和的抗凝血活性,其中化合物15f、15k、15n和150與陽性對照物達(dá)比加群(IC50= 1.23 nmol/L)相比較,具有相當(dāng)?shù)目鼓钚?其IC50值分別為1.81、3.21、3.69和2.16nmol/L。選取化合物15k以及150進(jìn)一步對其進(jìn)行體內(nèi)生物活性測試--對SD大鼠動靜脈血栓形成的影響,在所檢測的2種受試物中,均可有效抑制動靜脈血栓的栓子重量,且作用均與陽性對照物達(dá)比加群相當(dāng),抑制率分別為(76.23±3.68)%和(84.66±0.56)%,能夠作為抗凝血藥物候選藥物對其進(jìn)行更深層次的研究。
[Abstract]:The main content of this study is to combine the advantages of Darbica in anticoagulant therapy and the advantages of fluorine atom in drug molecular design. The computer aided drug design software (SYBYL-X 2.0. Tripos Inc.St. Louis) was used. The Surflex-Dock module with thrombin protein PDB: 1KTS as the receptor was used for the computer aided simulation and molecular docking of the derivatives of the Darbita group. Fluorine was introduced into the direct thrombin inhibitor Darby adders and modified with structure. A series of novel derivatives were designed and scored by computer simulation. A total of 15 compounds with high scoring value were selected, which were synthesized by Michael addition, acylation, reduction, condensation and closed loop Pinner reaction. Through screening the inhibition rate of these compounds, 11 derivatives were selected for in vitro anticoagulant activity test, the results showed that. All the compounds have stable and mild anticoagulant activity, of which compound 15fN 15k. The IC50 values of 15n and 150 were 1.81nmol / L and 1.81nmol / L, respectively, compared with those of the positive control group (IC 50 = 1.23 nmol / L). 3.69 and 2.16 nmol / L. selected compounds 15k and 150 to further test their bioactivity in vivo-the effect on arteriovenous thrombosis in SD rats. In the two tested samples, the embolus weight of arteriovenous thrombus was inhibited effectively, and the effect was similar to that of the positive control group. The inhibition rates were 76.23 鹵3.68% and 84.66 鹵0.56%, respectively, which could be further studied as anticoagulant drug candidates.
【學(xué)位授予單位】：上海應(yīng)用技術(shù)大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R91;R914.5;R96
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本文編號：1448744