苯并噻二嗪在两性离子磷脂细胞膜上的结构
Structure of benzothiadiazine at zwitterionic phospholipid cell membranes
摘要：
苯并噻二嗪是一种双环杂环苯衍生物，使用衍生自苯并噻二嗪的药物已成为高血压（用利尿剂（如苄氟噻嗪或氯噻嗪）治疗）、低血糖（用非利尿剂治疗）等疾病的广泛治疗方法。二氮嗪）或人类免疫缺陷病毒等。在这项工作中，我们研究了苯并噻二嗪与细胞膜和溶剂的基本成分，如磷脂，胆固醇，离子和水的相互作用。的相互微观相互作用的分析是至关重要的，以阐明的本地结构的苯并噻二嗪以及负责访问的苯并噻二嗪的内部的细胞的机制。我们已经进行了分子动力学模拟的苯并噻二嗪嵌入三种不同的模型两性离子双层膜由二肉豆蔻酰磷脂酰胆碱，二油酰磷脂酰胆碱，1，2-二油酰-sn-甘油-3-磷酸丝氨酸和胆固醇内的氯化钠水溶液中，以系统地研究微观相互作用的苯并噻二嗪与细胞膜在液晶相条件。从通过径向分布函数，氢键长度和基于可逆功计算的平均力的潜力获得的数据，我们已经观察到，苯并噻二嗪具有很强的亲和力，留在细胞膜界面，虽然它可以完全溶剂化的水在短时间内。此外，苯并噻二嗪能够通过不同特征长度的单氢键和双氢键结合脂质和胆固醇链。
英文摘要：
The use of drugs derived from benzothiadiazine, which is a bicyclic heterocyclic benzene derivative, has become a widespread treatment for diseases such as hypertension (treated with diuretics such as bendroflumethiazide or chlorothiazide), low blood sugar (treated with non-diuretic diazoxide) or the human immunodeficiency virus, among others. In this work we have investigated the interactions of benzothiadiazine with the basic components of cell membranes and solvents such as phospholipids, cholesterol, ions and water. The analysis of the mutual microscopic interactions is of central importance to elucidate the local structure of benzothiadiazine as well as the mechanisms responsible for the access of benzothiadiazine to the interior of the cell. We have performed molecular dynamics simulations of benzothiadiazine embedded in three different model zwitterionic bilayer membranes made by dimyristoilphosphatidylcholine, dioleoylphosphatidylcholine, 1,2- dioleoyl-sn-glycero-3-phosphoserine and cholesterol inside aqueous sodium-chloride solution in order to systematically examine microscopic interactions of benzothiadiazine with the cell membrane at liquid-crystalline phase conditions. From data obtained through radial distribution functions, hydrogen-bonding lengths and potentials of mean force based on reversible work calculations, we have observed that benzothiadiazine has a strong affinity to stay at the cell membrane interface although it can be fully solvated by water in short periods of time. Furthermore, benzothiadiazine is able to bind lipids and cholesterol chains by means of single and double hydrogen-bonds of different characteristic lengths.
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