【作者】 薛颖；

【导师】 王存新；

【作者基本信息】 北京工业大学 ， 流体力学， 2003， 硕士

【摘要】 随着计算机技术的飞速发展，计算机分子模拟在化学、生物化学以及分子生物学领域已经成为了十分重要和活跃的前沿课题。本文采用分子动力学模拟、量子力学从头算以及量子力学-分子力学相结合的多种方法对二胺基二硫醇类化合物 (99mTc-N2S2) 类脑显像配合物以及1-(5-氯吲哚-3-基)-3-羟基-3-(2-氢四唑-5-基) 丙烯酮 (5ClTEP) 类HIV-1整合酶抑制剂进行了综合研究。放射性核素脑显像技术在脑部疾病的医治中起着重要作用。通过计算表明， 99mTc-N2S2类配合物的脑吸收能力与它们的水化自由能相关。MD模拟结果显示BAT类配合物与MAMA类配合物的脑吸收值的大小依赖于它们的相对水化自由能；溶剂自洽反应场方法的计算结果表明同类配合物的脑吸收值取决于绝对水化自由能；QM/MM计算结果则证实了MAMA类配合物在水溶液中比BAT类配合物要稳定得多，因而更难以脱离水层穿越血脑屏障，而具有相对较小的脑吸收值。对HIV整合酶及其抑制剂的研究对抗艾滋病药物的研制具有重要意义。本论文通过模拟计算发现，5ClTEP分子主要是通过其中心的二酮酸 (3-羟基-3-丙烯酮) 对整合酶核心区a链中的活性氨基酸残基Glu152起到抑制作用，而与之相连的四唑基团和吲哚基团对5ClTEP与整合酶的结合起到稳定作用。此外5ClTEP抑制剂和Mg2+离子在与HIV-1整合酶的核心活性区域的作用中起着协同促进的抑制作用，二者的共同存在促进了体系的稳定性，并加强了对整合酶活性中心的作用能力。计算模拟还发现, 5ClTEP抑制剂中四唑基团对复合物体系的稳定作用远大于吲哚基团更多还原

【Abstract】 With the rapid development of computer technology, computer aided molecular modeling has become a very important and active task in chemistry, biochemistry and molecular biology. In this dissertation, molecular dynamics simulations, quantum mechanical ab initio calculations, together with quantum mechanical/molecular mechanical (QM/MM) method have been used to study the brain imaging agents of 99mTc-N2S2 complexes and HIV-1 integrase inhibitor 1-(5-(2-Chloroindol)-3-yl)-3- hydroxy-3-(2H-tetrazol-5-yl)-propenone (5ClTEP).Radical brain imaging agents play important roles in the medical treatment of brain diseases. In this study, we found that the brain uptakes of the 99mTc-N2S2 complexes were influenced by their hydrate free energies. The MD simulations showed that the differences between the brain uptakes of bisaminodithiol (BAT) and monoamino-monoamide dithiol (MAMA) complexes were determined by their relative hydrate free energies. The calculations of self-consistent reaction field (SCRF) method illustrated that the brain uptakes of the complexes relied on their absolute hydrate free energies. Furthermore, the QM/MM results approved that MAMA complexes were more stable than BAT complexes in aqueous solutions, hence the MAMA complexes were difficult to cross the the intact blood brain barrier (BBB) and had lower brain uptakes than BAT complexes. The BAT complexes are one kind of the promising brain imaging medicines.The study of HIV integrase inhibitors is important in the research of anti-AIDS medicines. The MD simulations showed that the key part of the inhibitor 5ClTEP is the<WP=5>aryl (-diketo function group, which was bounded to the active site of the HIV-1 integrase (residue Glu152), and achieved inhibiting effect in the HIV-infected cells. The existence of Mg2+ cation bought a stronger inhibiting effect to the inhibitor, and this experimental result was approved by our MD simulations, which showed that the inhibitor 5ClTEP cooperated with Mg2+ cation in the stability of the whole complex system. The tetrazol and indole function groups of 5ClTEP were also helpful in the stability of the integrase-inhibitor complex system, however, the simulating results showed that the tetrazol group was more important than the indole ring, which would make help in further drug design of anti-AIDS medicines更多还原