甾体类5α-还原酶抑制剂的量子化学与定量构效关系研究

【作者】 高伟；

【导师】 许旋；

【作者基本信息】 华南师范大学 ， 有机化学， 2002， 硕士

【摘要】 双氢睾丸激素DHT(dihydrotestosterone)被认为是体内最强的男性激素，是睾丸激素T(testosterone)的还原代谢产物，在这一还原过程中，5α-还原酶及其辅酶NADPH起着重要作用。体内过量DHT的存在是许多内分泌疾病的病因，将会导致前列腺癌和良性前列腺增生、粉刺、女性多毛症、女性男性秃顶等疾病。5α-还原酶抑制剂通过抑制T→DHT过程的发生，避免或减少产生活性更强的DHT，从而达到治疗的目的。 本文以55个甾体类的Ⅰ型的5α-还原酶抑制剂作为研究对象，采用分子力学，量子化学AM1方法计算分子电子结构，获得大量的分子结构参数和量化参数的数据，试图从中寻找药物的药效与结构的关系，探索药物的作用机制。 1)指出药物分子的4，6位置可能是分子与酶作用的活性区域；从前线分子轨道HOMO、LUMO的成分、净电荷、立体效应等方面，提出T或药物分子的0-21位以氢键与酶结合；从药物分子活性区域的LUMO成分平均化这一现象解释了1，2位、5，6位存在不饱和双键时，药物分子活性降低的原因。 2)发现疏水常数logP对药效影响较大，与药效的关系为一非线性关系，并用神经网络予以证实，讨论了影响logP的因素。 3)研究讨论了药物分子的电子结构与药效的关系，建立了较为显著的QSAR模型，发现分子和取代基的立体效应、疏水性质，C-17位置附近的净电荷是影响药效的主要因素。 我们的研究结果可用于指导实际药物的合成工作，又可以给我们研究药物的作用机理提供证据。更多还原

【Abstract】 The reduction of testosterone (T) to the dihydrotestosterone (DHT) is catalyzed by NADPH-dependent enzyme of steroid 5 a -reductase. DHT is considered as the most potent male sex hermone in the body. High levels of DHT is related to disorders such as BPH(benign prostatic hyperplasia), prostatic cancer, acne, pattern baldness and alopecia. Therefore, the blockade of formation of DHT by using enzyme inhibitors is a importance way in treating disorders related to high levels of DHT.In this paper, 55 analogs steroid compounds of 5 a -reductase enzyme( I ) inhibitors have been calculated by use of molecular mechanics and quantum chemistry methods AMI. We obtained a lot of data about molecular structure parameter and quantum chemistry parameter. We try to research for the relationships between activity and structure, explore the action mechanism of drugs.l)As for the compounds, site at 4,6 are the possible active area where drugs interacts with enzyme. The hydrogen-bond between O-21 of T or compounds and enzyme can be formed and explained it from Frontier Orbital densities and charges,stereo effect. From the average distribution of LUMO densities, We explained that the activity is decreased when unsaturation bond is located at site 1,2 or 5,6.2)The hydrophobicity is an important factor to affect the bioactivity in a non-linear way. We confirmed it by ANN(artificial neural network). The factors to affect the hydrophobicity were studied and discussed.3)We discussed the relationships between activity and structure. The significant QSAR models were set up. The stereo effect and hydrophobicity of molecular and substituents, the charge at site C-17 are the mainly factors to affect the activity.Our results can be helpful to both drugs synthesize and drugs action mechnism.更多还原