药物设计中卤键、胍基-精氨酸作用及药物合成反应过渡态的量子化学计算研究

发布时间：2018-04-13 13:01

本文选题：密度泛函理论 + 非共价相互作用　；参考：《中国科学院大学(中国科学院上海药物研究所)》2017年博士论文

【摘要】：量子化学是用量子力学的原理和方法处理化学问题的科学,目前已经发展成为化学以及相关学科在解释和预测分子结构和化学行为等方面的通用技术和手段。本论文包含两部分的研究内容,第一部分是量子化学计算方法在药物设计中的应用研究,具体包括第二章分子内卤键、第三章胍基-精氨酸配对作用和第四章药物合成中的反应机理的研究内容;第二部分为结核杆菌二氢叶酸还原酶DHFR抑制剂的发现(第五章),研究内容为利用分子对接和质谱等技术手段,预测并验证该重要结核病药物靶点的天然产物抑制剂。论文第一章为绪论,分别阐述了非共价相互作用的量子化学计算、药物设计中的卤键作用、基于片段的结核病药物设计研究背景。第二章围绕卤键的量子化学计算展开研究。在化学反应、物理现象及生命体系中,非共价相互作用都起着至关重要的作用。卤键(XB)则是由卤素原子(X=Cl、Br或I)作为路易斯酸,与中性或者带负电荷的路易斯碱(如O、N、S等)相互吸引,形成的一种非共价相互作用。分子间的卤键作用已被广泛报道,但分子内的卤键却鲜有研究。我们通过搜索剑桥晶体数据库(CSD)找到了具有典型分子内卤键作用的小分子结构。接着运用量子化学计算中的密度泛函理论(DFT)方法对小分子化合物进行结构优化与能量计算,研究不同取代基、不同溶剂对分子内卤键性质的影响。通过比较不同构象(是否含有分子内卤键)的能量差异,同时运用AIM(Atom in Molecule)理论分析键关键点(Bond Critical Point)处的电子密度、拉普拉斯电子密度等,我们确定了分子内卤键的存在;再采用自然键轨道(Natural Bond Orbital,NBO)理论分析确定卤键作用中电荷的转移情况,从而确定本研究中分子内卤键的作用强度在-1.66~-7.81 kcal/mol之间。在此基础上,我们使用CPCM(导电极化连续介质)的溶剂化模型,计算溶剂化效应下分子内的卤键作用,分析不同溶液中卤键对小分子pKa的影响,发现含有碘的分子内卤键结构与不含分子内卤键结构的相对pKa差值为-0.73;还采用COSMO模型,比较分子内卤键对小分子logP的影响,发现含分子内卤键的结构其logP值在正辛醇和水中的分配系数略高于不含分子内卤键的结构,为卤键在药物设计中的应用提供理论指导。论文的第三章围绕生物体中胍基配体与蛋白质体系的精氨酸残基之间形成的配对结构展开研究。通过数据库搜索,我们首次发现在蛋白质数据库(pdb,proteindatabank)中,一共存在227对在蛋白质配体和受体之间的带相同电荷的胍基对作用(胍基正离子与精氨酸配对,gdm+-arg对)。该发现表明,在含胍基药物和它们的靶标蛋白质之间确实可能存在胍基与精氨酸的结合作用。此外,通过对药品数据库(drugbank)的搜索,我们发现了145个含胍基的药物,这表明药物分子中,胍基是普遍存在的。另一些研究报告显示,在某一些分子结构中,引入胍基基团使其与蛋白质体系形成gdm+-arg对结构,可以使药物药效提高8倍以上。在上述研究调查的基础上,我们挑选出6个含有典型gdm+-arg对的配体-蛋白质复合物结构进行qm/mm计算。计算方法和基组为b97-d/6-311++g(d,p)。计算得到的胍基作用力强度在dmso和水中可以达到-1.0~-2.5kcal/mol,与普通分子间作用强度相当。计算结果也显示,随着介电常数的增加,gdm+-arg对的作用从排斥变为吸引,表明高介电常数的溶剂对gdm+-arg对存在一定的稳定作用。该研究显示,带相同电荷的gdm+-arg对之间的相互作用不仅可被用于调节药物先导化合物的物理化学性质,也能用于改善配体结合蛋白质受体的亲和力。论文的第四章使用密度泛函理论(dft)计算了两个药物合成反应的过渡态,对其机理展开研究,并辅以实验的支持。第一个反应中,我们研究了钯催化下新型c-h活化反应的反应机制,通过四并六双环的8-氨基喹啉类双齿导向基-钯-环状中间体结构的活化模式,突破了传统意义上只活化羰基β位的限制,发展了α位氧化反应的选择性。理论计算得到了不同反应路径中重要中间体的过渡态能量差异,显示出获得α及β两种氧化产物的难易程度,从而有效解释了反应机理。第二个反应中,我们通过计算吡啶酮类化合物合成反应中出现的季铵盐中间体与不同亲核试剂的反应,发现该反应具有良好的区域选择性。通过季铵盐与不同亲核试剂首先形成的过渡态结构的能垒高低可以判断反应的难易,从而实现对反应路径的预测。论文第五章围绕结核病靶点二氢叶酸还原酶dhfr的抑制剂发现展开研究。结核病是一种全球性的传染性疾病,每年造成两百万以上人口死亡。现阶段的结核病存在抗药性和多重耐药性等问题,使结核病的治疗面临更加严峻的问题。我们利用之前得到的10个结核病相关的蛋白靶点和从天然产物数据库中检测出的26个低分子量化合物相互作用形成的网络图,通过基于片段的药物设计的理念,将其中一个结核病靶点蛋白DHFR和与其有结合的片段化合物进行分子对接,找到小分子的结合位点并预测其相互结合模式。对接的结果中,如果某些片段化合物的结合位点与其它片段化合物明显不同,则将这些结合模式特殊的分子固定于蛋白口袋的结合位置,再将其它片段化合物对接到靶点蛋白和固定片段化合物的复合物的口袋中。将片段化合物单独对接与对接到复合物中的作用模式进行对比分析,找出结合模式相似的化合物,说明这些化合物和固定在蛋白口袋中的片段化合物可能同时结合到蛋白口袋中。再用傅里叶变换的质谱方法(FTMS)对分子对接结果进行验证,用实验方法找出可以同时与结核病靶点蛋白DHFR结合的两个片段化合物。质谱实验发现四对化合物可以单独或同时与Mtb DHFR蛋白结合。对接结果与实验结果十分吻合。第六章为总结与展望。
[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.

【学位授予单位】：中国科学院大学(中国科学院上海药物研究所)
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R91

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