In silico prediction of drug solubility: 2. Free energy of solvation in pure melts.
In silico prediction of drug solubility: 2. Free energy of solvation in pure melts.
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药物溶解度的计算机预测：2.纯熔体中的溶剂化自由能。
DOI：
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发表时间：
2007
影响因子：
3.3
通讯作者：
R. Kjellander
中科院分区：
文献类型：
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作者：
Kai Lüder;L. Lindfors;J. Westergren;S. Nordholm;R. Kjellander
药物在水中的溶解度在一系列的论文和当前的工作中被研究。用自由能微扰法计算了46个药物分子在673.15 K(400℃)纯药物熔体中的溶剂化自由能DeltaG*(VL)。模拟分两个步骤进行，首先是库仑相互作用，然后是Lennard-Jones相互作用，从完全相互作用缩小到没有相互作用。用理论解释了结果，假设DeltaG*(VL)=DeltaG(Cav)+E(Lj)+E(C)/2，其中这些纯药物体系中空穴形成的自由能DeltaG(Cav)是用硬体理论得到的，E(Lj)和E(C)分别是一个分子与另一个分子的Lennard-Jones和Coulomb相互作用能。由于硬体理论中的主要参数是体积分数，因此采用状态方程方法估算分子体积。使用硬扁平理论获得了令人满意的结果，其中扁平轴比是根据模拟得到的分子表面积和体积来计算的。库仑项E(C)/2是库仑能量的一半，符合线性响应，这与我们的模拟结果很好地吻合。与我们以前关于水化自由能的结果相比，纯药物体系中的库仑相互作用较弱，而范德华相互作用起着更重要的作用。
The solubility of drugs in water is investigated in a series of papers and in the current work. The free energy of solvation, DeltaG*(vl), of a drug molecule in its pure drug melt at 673.15 K (400 degrees C) has been obtained for 46 drug molecules using the free energy perturbation method. The simulations were performed in two steps where first the Coulomb and then the Lennard-Jones interactions were scaled down from full to no interaction. The results have been interpreted using a theory assuming that DeltaG*(vl) = DeltaG(cav) + E(LJ) + E(C)/2 where the free energy of cavity formation, DeltaG(cav), in these pure drug systems was obtained using hard body theories, and E(LJ) and E(C) are the Lennard-Jones and Coulomb interaction energies, respectively, of one molecule with the other ones. Since the main parameter in hard body theories is the volume fraction, an equation of state approach was used to estimate the molecular volume. Promising results were obtained using a theory for hard oblates, in which the oblate axial ratio was calculated from the molecular surface area and volume obtained from simulations. The Coulomb term, E(C)/2, is half of the Coulomb energy in accord with linear response, which showed good agreement with our simulation results. In comparison with our previous results on free energy of hydration, the Coulomb interactions in pure drug systems are weaker, and the van der Waals interactions play a more important role.