Studies on the Molecular Mechanics Calculation of Drugs Including Simulation of Infrared and Raman Spectra

分子力学计算作为研究药物构效关系的一种新方法，引起了人们的广泛关注。然而，对于复杂的极性分子，在孤立状态下很难获得热力学和结构数据。为了克服这一困难，本项目的目标是利用液体或结晶态的红外和拉曼光谱的频率和强度的信息。到目前为止所取得的结果如下：1.有效原子电荷通量已被用作阐明红外吸收强度的基本参数。引入这些通量作为势能参数，同时拟合了饱和烃、醚、酮和醛的平衡结构、热力学函数、偶极矩以及红外光谱和拉曼光谱。考虑分子间力的影响，对苯甲酸和对氟苯甲酸的混晶进行了分子力学计算。这一结果与这两个组分形成固体溶液的事实是一致的。以前用于苯甲酸和阿司匹林的法坐标分析的氢键势模型已被略微修改，以适应脂肪酸二聚体的离解能和结构。并在此模型的基础上对二聚化过程中红外光谱的变化进行了解释。为了模拟结晶态药物大分子的红外和拉曼光谱，开发了一种算法，在计算弹性常数时包括给定数目的低频模式。将该方法应用于甘氨酸晶体，揭示了某些简正波对弹性常数的特殊影响。

Molecular mechanics calculation has drawn attention as a new approach to the study of structure-activity relationship of drugs. For complex polar molecules, however, the theromodynamical and structural data are hardly available in the isolated state. To overcome this difficulty, the present project has been planned to aim at utilizing the information on both the frequencies and the intensities of infrared and Raman spectra in the liquid or the crystalline state. The results so far obtained are as follows.1. The fluxes of effective atomic charges have been used as essential parameters for elucidating infrared absorption intensities. Introducing these fluxes also as the potential parameters, the equilibrium structures, the thermodynamic functions, the dipole moments and the infrared and Raman spectra of saturated hydrocarbons, ethers, ketones and aldehydes have been simulaneously fitted.2. Molecular mechanics calculation including the effect of intermolecular forces has been applied to the mixed crystals of benzoic acid and p-fluorobenzoic acid. The result is compatible with the fact that these two components form a solid solution.3. The potential model of hydrogen bonds previously used for the normal coordinates analysis of benzoic acid and aspirin has been slightly modified to fit the dissociation energy and the structure of fatty acid dimers. The changes of infrared spectra on dimerization have also been elucidated on the basis of this model.4. To simulate infrared and Raman spectra of large drug molecules in the crystalline state, an algorithm has been developed to include a given numer of low-frequency modes in the calculation of elastic constants. A specific effect of some normal modes on the elastic constants has been revealed by applying this method to -glycine crystal.