权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

PREDICTION OF STRUCTURES AND BINDING CONSTANTS OF DRUG-RECEPTOR COMPLEXES BY HYDROPHOBIC SURFACE AREAS

通过疏水表面区域预测药物受体复合物的结构和结合常数

基本信息

批准号：
11672153
负责人：
FUNASAKI Noriaki
金额：
$ 0.77万
依托单位：
KYOTO PHARMACEUTICAL UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672153/
关键词：
molecular surface area binding constant hydrophobicity complex drug receptor molecular structure

项目摘要

1. We developed a computer software to calculate the decrease of molecular surface area with docking of host and gust and applied it to predict the structure and the binding constant of their complex. The structure in which this decreased area has the maximum is the most stable and the binding constant is uniquely correlated with this area, regardless of various host-guest systems. This finding allows us to predict the structure and binding constant from the chemical structures of host and guest.2. The structure of oxyphenonium bromide in water was estimated from the maximum hydrophilic surface area and the minimum hydrophobic surface area. This structure was in excellent agreement with the NMR structure, though the molecular mechanics structure was slightly different from it. This fact demonstrates that the molecular mechanics calculation does not account for the hydration energy and should include this energy estimated from molecular surface areas.3. We developed the NMR method for binding constant determination. The NMR chemical shift referred to external standard must be corrected for the change in volume magnetic susceptibility. This correction gave a correct binding constant. We proposed two internal standards for anionic compounds. Furthermore, the binding constants for multiple equilibrium systems have been determined and were analyzed on the basis of the structures of complexes.4. We have demonstrated that the suppression of bitterness and hemolysis of drug by cyclodextrin is predictable from observed surface tensions or electromotive forces, regardless of the kind and concentration of cyclodextrin. These observed values directly correspond to the concentration of free drug molecule in the cyclodextrin solution.5. The present results serve for predicting the structure and binding constant of complexes, such as drug-receptor and enzyme-substrate, from the chemical structures of host and guest and will enable a rapid design of new drug and new formulation.

1.我们开发了一个计算机软件来计算宿主和阵风对接后分子表面积的减小，并应用该软件预测了它们的复合物的结构和结合常数。在该结构中，该减少的面积具有最大值是最稳定的，并且结合常数与该面积唯一相关，而与各种主客体系统无关。这一发现使我们能够从主客体的化学结构预测其结构和结合常数.根据最大亲水表面积和最小疏水表面积估算了氧苯溴铵在水中的结构。这一结构与NMR结构非常一致，尽管分子力学结构与NMR结构略有不同，这一事实表明分子力学计算不考虑水化能，而应包括由分子表面积估算的水化能.我们发展了核磁共振法测定结合常数。NMR化学位移参考外部标准必须校正体积磁化率的变化。该校正给出了正确的结合常数。我们提出了两种阴离子化合物的内标。此外，还测定了多平衡体系的结合常数，并根据配合物的结构进行了分析.我们已经证明，无论环糊精的种类和浓度如何，环糊精对药物的苦味和溶血的抑制都可以从观察到的表面张力或电动势来预测。这些观察值直接对应于环糊精溶液中游离药物分子的浓度。本研究结果可用于从主客体的化学结构预测药物-受体、酶-底物等复合物的结构和结合常数，为新药和新剂型的快速设计提供依据。