本文選題：密度泛函理論 + 非共價(jià)相互作用�。� 參考：《中國(guó)科學(xué)院大學(xué)(中國(guó)科學(xué)院上海藥物研究所)》2017年博士論文

【摘要】：量子化學(xué)是用量子力學(xué)的原理和方法處理化學(xué)問題的科學(xué),目前已經(jīng)發(fā)展成為化學(xué)以及相關(guān)學(xué)科在解釋和預(yù)測(cè)分子結(jié)構(gòu)和化學(xué)行為等方面的通用技術(shù)和手段。本論文包含兩部分的研究?jī)?nèi)容,第一部分是量子化學(xué)計(jì)算方法在藥物設(shè)計(jì)中的應(yīng)用研究,具體包括第二章分子內(nèi)鹵鍵、第三章胍基-精氨酸配對(duì)作用和第四章藥物合成中的反應(yīng)機(jī)理的研究?jī)?nèi)容;第二部分為結(jié)核桿菌二氫葉酸還原酶DHFR抑制劑的發(fā)現(xiàn)(第五章),研究?jī)?nèi)容為利用分子對(duì)接和質(zhì)譜等技術(shù)手段,預(yù)測(cè)并驗(yàn)證該重要結(jié)核病藥物靶點(diǎn)的天然產(chǎn)物抑制劑。論文第一章為緒論,分別闡述了非共價(jià)相互作用的量子化學(xué)計(jì)算、藥物設(shè)計(jì)中的鹵鍵作用、基于片段的結(jié)核病藥物設(shè)計(jì)研究背景。第二章圍繞鹵鍵的量子化學(xué)計(jì)算展開研究。在化學(xué)反應(yīng)、物理現(xiàn)象及生命體系中,非共價(jià)相互作用都起著至關(guān)重要的作用。鹵鍵(XB)則是由鹵素原子(X=Cl、Br或I)作為路易斯酸,與中性或者帶負(fù)電荷的路易斯堿(如O、N、S等)相互吸引,形成的一種非共價(jià)相互作用。分子間的鹵鍵作用已被廣泛報(bào)道,但分子內(nèi)的鹵鍵卻鮮有研究。我們通過搜索劍橋晶體數(shù)據(jù)庫(kù)(CSD)找到了具有典型分子內(nèi)鹵鍵作用的小分子結(jié)構(gòu)。接著運(yùn)用量子化學(xué)計(jì)算中的密度泛函理論(DFT)方法對(duì)小分子化合物進(jìn)行結(jié)構(gòu)優(yōu)化與能量計(jì)算,研究不同取代基、不同溶劑對(duì)分子內(nèi)鹵鍵性質(zhì)的影響。通過比較不同構(gòu)象(是否含有分子內(nèi)鹵鍵)的能量差異,同時(shí)運(yùn)用AIM(Atom in Molecule)理論分析鍵關(guān)鍵點(diǎn)(Bond Critical Point)處的電子密度、拉普拉斯電子密度等,我們確定了分子內(nèi)鹵鍵的存在;再采用自然鍵軌道(Natural Bond Orbital,NBO)理論分析確定鹵鍵作用中電荷的轉(zhuǎn)移情況,從而確定本研究中分子內(nèi)鹵鍵的作用強(qiáng)度在-1.66~-7.81 kcal/mol之間。在此基礎(chǔ)上,我們使用CPCM(導(dǎo)電極化連續(xù)介質(zhì))的溶劑化模型,計(jì)算溶劑化效應(yīng)下分子內(nèi)的鹵鍵作用,分析不同溶液中鹵鍵對(duì)小分子pKa的影響,發(fā)現(xiàn)含有碘的分子內(nèi)鹵鍵結(jié)構(gòu)與不含分子內(nèi)鹵鍵結(jié)構(gòu)的相對(duì)pKa差值為-0.73;還采用COSMO模型,比較分子內(nèi)鹵鍵對(duì)小分子logP的影響,發(fā)現(xiàn)含分子內(nèi)鹵鍵的結(jié)構(gòu)其logP值在正辛醇和水中的分配系數(shù)略高于不含分子內(nèi)鹵鍵的結(jié)構(gòu),為鹵鍵在藥物設(shè)計(jì)中的應(yīng)用提供理論指導(dǎo)。論文的第三章圍繞生物體中胍基配體與蛋白質(zhì)體系的精氨酸殘基之間形成的配對(duì)結(jié)構(gòu)展開研究。通過數(shù)據(jù)庫(kù)搜索,我們首次發(fā)現(xiàn)在蛋白質(zhì)數(shù)據(jù)庫(kù)(pdb,proteindatabank)中,一共存在227對(duì)在蛋白質(zhì)配體和受體之間的帶相同電荷的胍基對(duì)作用(胍基正離子與精氨酸配對(duì),gdm+-arg對(duì))。該發(fā)現(xiàn)表明,在含胍基藥物和它們的靶標(biāo)蛋白質(zhì)之間確實(shí)可能存在胍基與精氨酸的結(jié)合作用。此外,通過對(duì)藥品數(shù)據(jù)庫(kù)(drugbank)的搜索,我們發(fā)現(xiàn)了145個(gè)含胍基的藥物,這表明藥物分子中,胍基是普遍存在的。另一些研究報(bào)告顯示,在某一些分子結(jié)構(gòu)中,引入胍基基團(tuán)使其與蛋白質(zhì)體系形成gdm+-arg對(duì)結(jié)構(gòu),可以使藥物藥效提高8倍以上。在上述研究調(diào)查的基礎(chǔ)上,我們挑選出6個(gè)含有典型gdm+-arg對(duì)的配體-蛋白質(zhì)復(fù)合物結(jié)構(gòu)進(jìn)行qm/mm計(jì)算。計(jì)算方法和基組為b97-d/6-311++g(d,p)。計(jì)算得到的胍基作用力強(qiáng)度在dmso和水中可以達(dá)到-1.0~-2.5kcal/mol,與普通分子間作用強(qiáng)度相當(dāng)。計(jì)算結(jié)果也顯示,隨著介電常數(shù)的增加,gdm+-arg對(duì)的作用從排斥變?yōu)槲?表明高介電常數(shù)的溶劑對(duì)gdm+-arg對(duì)存在一定的穩(wěn)定作用。該研究顯示,帶相同電荷的gdm+-arg對(duì)之間的相互作用不僅可被用于調(diào)節(jié)藥物先導(dǎo)化合物的物理化學(xué)性質(zhì),也能用于改善配體結(jié)合蛋白質(zhì)受體的親和力。論文的第四章使用密度泛函理論(dft)計(jì)算了兩個(gè)藥物合成反應(yīng)的過渡態(tài),對(duì)其機(jī)理展開研究,并輔以實(shí)驗(yàn)的支持。第一個(gè)反應(yīng)中,我們研究了鈀催化下新型c-h活化反應(yīng)的反應(yīng)機(jī)制,通過四并六雙環(huán)的8-氨基喹啉類雙齒導(dǎo)向基-鈀-環(huán)狀中間體結(jié)構(gòu)的活化模式,突破了傳統(tǒng)意義上只活化羰基β位的限制,發(fā)展了α位氧化反應(yīng)的選擇性。理論計(jì)算得到了不同反應(yīng)路徑中重要中間體的過渡態(tài)能量差異,顯示出獲得α及β兩種氧化產(chǎn)物的難易程度,從而有效解釋了反應(yīng)機(jī)理。第二個(gè)反應(yīng)中,我們通過計(jì)算吡啶酮類化合物合成反應(yīng)中出現(xiàn)的季銨鹽中間體與不同親核試劑的反應(yīng),發(fā)現(xiàn)該反應(yīng)具有良好的區(qū)域選擇性。通過季銨鹽與不同親核試劑首先形成的過渡態(tài)結(jié)構(gòu)的能壘高低可以判斷反應(yīng)的難易,從而實(shí)現(xiàn)對(duì)反應(yīng)路徑的預(yù)測(cè)。論文第五章圍繞結(jié)核病靶點(diǎn)二氫葉酸還原酶dhfr的抑制劑發(fā)現(xiàn)展開研究。結(jié)核病是一種全球性的傳染性疾病,每年造成兩百萬以上人口死亡。現(xiàn)階段的結(jié)核病存在抗藥性和多重耐藥性等問題,使結(jié)核病的治療面臨更加嚴(yán)峻的問題。我們利用之前得到的10個(gè)結(jié)核病相關(guān)的蛋白靶點(diǎn)和從天然產(chǎn)物數(shù)據(jù)庫(kù)中檢測(cè)出的26個(gè)低分子量化合物相互作用形成的網(wǎng)絡(luò)圖,通過基于片段的藥物設(shè)計(jì)的理念,將其中一個(gè)結(jié)核病靶點(diǎn)蛋白DHFR和與其有結(jié)合的片段化合物進(jìn)行分子對(duì)接,找到小分子的結(jié)合位點(diǎn)并預(yù)測(cè)其相互結(jié)合模式。對(duì)接的結(jié)果中,如果某些片段化合物的結(jié)合位點(diǎn)與其它片段化合物明顯不同,則將這些結(jié)合模式特殊的分子固定于蛋白口袋的結(jié)合位置,再將其它片段化合物對(duì)接到靶點(diǎn)蛋白和固定片段化合物的復(fù)合物的口袋中。將片段化合物單獨(dú)對(duì)接與對(duì)接到復(fù)合物中的作用模式進(jìn)行對(duì)比分析,找出結(jié)合模式相似的化合物,說明這些化合物和固定在蛋白口袋中的片段化合物可能同時(shí)結(jié)合到蛋白口袋中。再用傅里葉變換的質(zhì)譜方法(FTMS)對(duì)分子對(duì)接結(jié)果進(jìn)行驗(yàn)證,用實(shí)驗(yàn)方法找出可以同時(shí)與結(jié)核病靶點(diǎn)蛋白DHFR結(jié)合的兩個(gè)片段化合物。質(zhì)譜實(shí)驗(yàn)發(fā)現(xiàn)四對(duì)化合物可以單獨(dú)或同時(shí)與Mtb DHFR蛋白結(jié)合。對(duì)接結(jié)果與實(shí)驗(yàn)結(jié)果十分吻合。第六章為總結(jié)與展望。
[Abstract]:Quantum chemistry is the treatment of chemical problems with the principle and method of quantum mechanics science, has now become the chemistry and related disciplines to explain and predict the molecular structure and chemical behavior of the general techniques and methods. This thesis consists of two parts of the research contents, the first part is the application of quantum chemical methods in drug design the second chapter, including the intramolecular halogen bond, research content of reaction mechanism of arginine pairing function and the fourth chapter in the third chapter of drug synthesis of guanidine; the second part of the discovery of Mycobacterium tuberculosis dihydrofolate reductase inhibitors of DHFR (the fifth chapter), the research content is using molecular docking and mass spectrometry techniques to predict and verify the natural the important product inhibitor TB drug targets. The first chapter is the introduction, respectively expounds the quantum chemical calculation of non covalent interactions, drug Halogen bonds in the design of TB drug design research background fragments based on quantum chemistry. The second chapter focuses on the calculation of halogen bond is researched. In chemical reaction, physical phenomena and life system, non covalent interactions play a crucial role. Halogen bond (XB) is composed of a halogen atom (X=Cl, Br or I) as Lewis acid, neutral or negative charge and with Lewis base (such as O, N, S etc.) are attracted to each other, a non covalent interaction. The formation of halogen bond intermolecular interactions have been widely reported, but the intramolecular halogen bond is rarely studied. We search through the Cambridge crystal the database (CSD) to find a small molecular structure with typical intramolecular halogen bond. Then by using the density functional theory in quantum chemistry calculation (DFT) method was used to optimize the structure and energy calculation of small molecular compound of different substituents, different solvents on intramolecular Effect of halogen bonding properties. By comparing the different conformation (containing intramolecular halogen bond) energy difference, while the use of AIM (Atom in Molecule) theory analysis of key points (Bond Critical Point) the electron density of the Laplasse electron density, we determine the intramolecular halogen bond exists; then the natural bond track (Natural Bond Orbital, NBO) theoretical analysis to determine the charge transfer effect of halogen bond, so as to determine the intensity of molecules in this study in the halogen bond in -1.66~-7.81 kcal/mol. On this basis, we use CPCM (conductive polarizable continuum) solvation model, calculation of halogen bonds molecular solvation effect the analysis of the effect of halogen bond in different solutions for small molecule pKa, found that the halogen bond structure of molecular iodine containing and not containing halogen bond in the molecule structure of relative difference was -0.73 pKa; using COSMO model, comparison Effect in halogen bonding of small molecule logP, found that the structure with intramolecular halogen bond and its logP value distribution coefficient in octanol and water is slightly higher than the structure without intramolecular halogen bond, to provide theoretical guidance for the application of halogen bond in drug design. Research on the structure formed between the third chapter the organisms in guanidine based ligands and protein system arginine residues. Through database search, we first found in protein databases (PDB, proteindatabank), there were a total of 227 of the protein between the ligand and the receptor with the same charge of positive ions (guanidine guanidine and arginine on gdm+-arg pairing). The findings suggest that between guanidine containing drugs and their target proteins may indeed exist with arginine guanidino binding acid. In addition, the drug database (drugbank) search, we found 145 This shows that the guanidino containing drugs, drug molecules, guanidine is widespread. Some other research report shows that in some of the molecular structure, introducing guanidine groups to form gdm+-arg on the structure and protein system, can make the drugs increase more than 8 times. Based on the above research, we selected 6 a typical gdm+-arg structure containing ligand of the protein complexes of qm/mm. The calculation method and basis set for b97-d/6-311++g (D, P). The calculated guanidino force strength can reach -1.0~-2.5kcal/mol and DMSO in the water, and the general strength between molecules. The results also showed that with the increase of dielectric constant. Effect of gdm+-arg on from repulsion to attraction, showed a high dielectric constant solvent of gdm+-arg to stable effect. The study shows that with the same charge gdm+-arg on the interaction between Not only can be used to regulate the physical and chemical properties of lead compounds, can also be used to improve the affinity of the receptor ligand binding protein. In the fourth chapter, using the density functional theory (DFT) transition state two drug synthesis reaction were calculated and studied the mechanism, along with experimental support. The first reaction. We have studied the reaction mechanism of new palladium catalyzed by C-H activation by 8- aminoquinolines, four and six bis bidentate palladium base oriented cyclic intermediate structure activation mode, break through the traditional sense only limit the activation of carbonyl beta, the development of selective alpha oxidation reaction. Theoretical calculation has been the transition state energy difference is an important intermediate in different reaction paths, showing the degree of difficulty of obtaining alpha and beta two oxidation products, so as to effectively explain the reaction mechanism. Second reactions, we Calculation of pyridone compounds in the synthesis reaction of quaternary ammonium intermediates with different nucleophiles reaction, the reaction with high regioselectivity. The structure transition state through quaternary ammonium salt with different nucleophiles first formed the energy barrier height can determine the reaction easily, so as to realize the prediction of the reaction path of the fifth. Chapter around the target dihydrofolate reductase inhibitor tuberculosis DHFR discovery research. Tuberculosis is a global infectious disease, caused each year more than two million of the population died. At the present stage tuberculosis drug resistance and multi drug resistance, so that the treatment of tuberculosis is facing more severe problems. We use the network diagram before the 10 TB related the target protein and 26 low molecular weight compounds detected from natural products database in the form of interaction, through The drug design based on the concept of fragments, which will be a target of tuberculosis protein DHFR and its fragment binding of compounds by molecular docking, find a small molecule binding site and its combination model. The results of docking, if some fragments of compounds binding sites and other fragments of compounds will be significantly different with the location of the binding mode of special molecules fixed on the protein pocket, and the pocket other fragments compounds on the complex received target proteins and fixed fragment compounds. The compounds will be docking with the docking to separate fragments of mode of action in the complexes were analyzed, and find out the similar patterns of these compounds, and compounds fixed in the pocket protein fragment compound may also bind to the protein pocket. Then Fourier transform mass spectrometry (FTMS) on the The results are verified by experimental method can find two compounds simultaneously with the target fragment of tuberculosis protein DHFR binding. Mass spectrometry experiments found that four of compounds can be individually or simultaneously with Mtb DHFR binding protein. The docking results agree well with the experimental data. The sixth chapter is the summary and outlook.

【學(xué)位授予單位】：中國(guó)科學(xué)院大學(xué)(中國(guó)科學(xué)院上海藥物研究所)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R91

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