以乙酰膽堿酯酶為靶標的虛擬篩選研究
發(fā)布時間：2018-12-23 20:54
【摘要】：阿爾茨海默病(Alzheimer's disease, AD)是嚴重威脅當(dāng)代老年人健康的疾病,導(dǎo)致中樞神經(jīng)系統(tǒng)進行性退變進而影響患者的認知功能、記憶功能、語言功能、視空間功能,所以也被稱為老年癡呆癥。然而,老年癡呆癥的發(fā)病機制還不是十分清楚,有待更加深入詳細的研究。膽堿不足是導(dǎo)致阿爾茨海默病產(chǎn)生的一個主要原因,因此具有增強膽堿作用的藥物在老年癡呆癥的治療方面發(fā)揮了重要作用。目前治療AD的主要藥物有他克林(Tacrine)、利伐斯的(Rivastigmine)、石杉堿甲(Hu-perzineA)、多奈哌齊(Donepezil)等,它們都是通過與乙酰膽堿酯酶(AChE)結(jié)合,對酶活性產(chǎn)生抑制作用,達到一定的治療效果。然而現(xiàn)有的商品化的AChE抑制劑的臨床效果有限,并且在治療過程中都伴隨著不同程度的毒副作用,尋找新型高活性的AChE抑制劑小分子是很有必要的。 他克林褪黑激素雜合體系列抑制劑小分子對人體乙酰膽堿酯酶(h-AChE)均呈現(xiàn)出很高的抑制活性,明顯高于之前已報道的系列藥物分子,達到了pM級別。本文從該系列高活性化合物出發(fā),通過分子對接后,進行受體和配體結(jié)合自由能的計算,發(fā)現(xiàn)結(jié)合自由能的計算值和生物測試活性值有很好的線性相關(guān)性,確定了分子對接結(jié)合模式的正確性。通過對結(jié)合自由能的能量分解,可以找到配體與人體乙酰膽堿酯酶(h-AChE)相互作用中起關(guān)鍵作用的重要氨基酸殘基。 通過基于受體的藥效團模型(Structure Based Pharmacophore,SBP)生成藥效團模型,參照之前確定的活性腔中重要的氨基酸殘基,對生成的藥效團中重要的元素特征進行保留,然后將前期的系列高活性分子和未知活性的分子組成分子庫對藥效團的合理性進行驗證,高活性分子可以被很好的篩選出來,驗證了我們構(gòu)建的藥效團模型的有效性。最后將該藥效團對自己構(gòu)建的分子庫進行虛擬篩選,篩選到含有他克林環(huán)、含有酰胺鍵的亞甲基長鏈以及香豆素環(huán)片段的化合物分子,通過分子對接了解該類化合物分子與受體蛋白的合理結(jié)合模式,然后對該類分子進行生物活性測試,發(fā)現(xiàn)他們均具有活較好的活性,其中最優(yōu)的分子其體外酶活相對經(jīng)典抑制劑他克林提高了一倍多,為今后抑制劑分子的優(yōu)化提供了重要的指導(dǎo)意義。
[Abstract]:Alzheimer's disease (Alzheimer's disease, AD) is a serious threat to the health of the elderly, leading to progressive degeneration of the central nervous system, which affects the cognitive function, memory function, language function, visual and spatial function of the patient. So it's also called Alzheimer's disease. However, the pathogenesis of Alzheimer's disease is not very clear, need more in-depth and detailed research. Choline deficiency is a major cause of Alzheimer's disease, so drugs that enhance choline play an important role in the treatment of Alzheimer's disease. At present, the main drugs used in the treatment of AD are (Rivastigmine), Huperzine A (Hu-perzineA) of tacrine (Tacrine), Livas, Donepezil (Donepezil) and so on. They all inhibit the enzyme activity by binding with acetylcholinesterase (AChE). To achieve a certain therapeutic effect. However, the clinical effects of commercial AChE inhibitors are limited, and in the course of treatment, with varying degrees of toxic side effects, it is necessary to find new and highly active small molecules of AChE inhibitors. The small molecules of tacrine melatonin heterozyme showed high inhibitory activity on human acetylcholinesterase (h-AChE), which was significantly higher than that of the previously reported series of drug molecules, and reached the pM level. Starting from this series of highly active compounds, the binding free energy of receptor and ligand was calculated by molecular docking. It was found that there was a good linear correlation between the calculated value of binding free energy and the bioassay activity value. The correctness of the molecular docking mode was determined. Through the energy decomposition of binding free energy, the important amino acid residues that play a key role in the interaction between ligand and human acetylcholinesterase (h-AChE) can be found. The pharmacophore model was generated by receptor-based pharmacophore model (Structure Based Pharmacophore,SBP), and the important elemental characteristics of the generated pharmacophore were preserved by referring to the important amino acid residues in the previously determined active cavity. Then, the rationality of the pharmacophore was verified by a series of molecular libraries of high active molecules and unknown active molecules, and the high active molecules could be well screened out, which verified the validity of the pharmacophore model we constructed. Finally, the pharmacophore was used for virtual screening of the constructed molecular library, and the compounds containing tacrine ring, methylene chain containing amide bond and coumarin ring fragment were screened out. Through molecular docking to understand the reasonable binding mode between the molecules and receptor proteins, and then to test the bioactivity of these molecules, we found that they all have good activity. The in vitro enzyme activity of the optimal molecule is more than double that of the classical inhibitor tacrine, which provides important guidance for the optimization of the inhibitor molecule in the future.
【學(xué)位授予單位】：華中師范大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2013
【分類號】：R749.16
[Abstract]:Alzheimer's disease (Alzheimer's disease, AD) is a serious threat to the health of the elderly, leading to progressive degeneration of the central nervous system, which affects the cognitive function, memory function, language function, visual and spatial function of the patient. So it's also called Alzheimer's disease. However, the pathogenesis of Alzheimer's disease is not very clear, need more in-depth and detailed research. Choline deficiency is a major cause of Alzheimer's disease, so drugs that enhance choline play an important role in the treatment of Alzheimer's disease. At present, the main drugs used in the treatment of AD are (Rivastigmine), Huperzine A (Hu-perzineA) of tacrine (Tacrine), Livas, Donepezil (Donepezil) and so on. They all inhibit the enzyme activity by binding with acetylcholinesterase (AChE). To achieve a certain therapeutic effect. However, the clinical effects of commercial AChE inhibitors are limited, and in the course of treatment, with varying degrees of toxic side effects, it is necessary to find new and highly active small molecules of AChE inhibitors. The small molecules of tacrine melatonin heterozyme showed high inhibitory activity on human acetylcholinesterase (h-AChE), which was significantly higher than that of the previously reported series of drug molecules, and reached the pM level. Starting from this series of highly active compounds, the binding free energy of receptor and ligand was calculated by molecular docking. It was found that there was a good linear correlation between the calculated value of binding free energy and the bioassay activity value. The correctness of the molecular docking mode was determined. Through the energy decomposition of binding free energy, the important amino acid residues that play a key role in the interaction between ligand and human acetylcholinesterase (h-AChE) can be found. The pharmacophore model was generated by receptor-based pharmacophore model (Structure Based Pharmacophore,SBP), and the important elemental characteristics of the generated pharmacophore were preserved by referring to the important amino acid residues in the previously determined active cavity. Then, the rationality of the pharmacophore was verified by a series of molecular libraries of high active molecules and unknown active molecules, and the high active molecules could be well screened out, which verified the validity of the pharmacophore model we constructed. Finally, the pharmacophore was used for virtual screening of the constructed molecular library, and the compounds containing tacrine ring, methylene chain containing amide bond and coumarin ring fragment were screened out. Through molecular docking to understand the reasonable binding mode between the molecules and receptor proteins, and then to test the bioactivity of these molecules, we found that they all have good activity. The in vitro enzyme activity of the optimal molecule is more than double that of the classical inhibitor tacrine, which provides important guidance for the optimization of the inhibitor molecule in the future.
【學(xué)位授予單位】：華中師范大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2013
【分類號】：R749.16
【共引文獻】
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