Díaz Natalia, Sordo Tomás L, Suárez Dimas, Méndez Rosa, Villacorta Javier Martín, Simón Luis, Rico Manuel, Jiménez M Angeles
Departamento de Química Física y Analítica, Universidad de Oviedo, Julian Clavería 8, 33006 Oviedo (Asturias), Spain.
J Med Chem. 2006 Jun 1;49(11):3235-43. doi: 10.1021/jm060096t.
Herein we examine the viability of physicochemical approaches based on standard computational chemistry tools to characterize the structure and energetics of flexible drug molecules with various titratable sites. We focus on the case of the monobactam antibiotic aztreonam, whose structure and physicochemical properties have been ascribed to several tautomeric forms, although it is still unclear which protonation states are responsible for its biological activity. First, we experimentally determined the pKa values for aztreonam over the pH range 0.8-7.0 using both 1H NMR and 13C NMR spectroscopy. Second, we carried out quantum chemical calculations on snapshots extracted from classical molecular dynamics simulations. Various levels of approximation were used in the energy calculations: ONIOM(HF/3-21G*:AMBER) for geometry relaxation, B3LYP/6-31+G** for electronic and electrostatic solvation energies, and molecular mechanics for attractive dispersion energy. The value of the free energy of solvation of a proton was treated as a parameter and chosen to give the best match between calculated and experimental pKa values for small molecules. Overall, this computational scheme can give satisfactory results in the pKa calculations for drug molecules.
在此，我们研究基于标准计算化学工具的物理化学方法用于表征具有各种可滴定位点的柔性药物分子的结构和能量学的可行性。我们聚焦于单环β-内酰胺抗生素氨曲南的情况，其结构和物理化学性质归因于几种互变异构形式，尽管仍不清楚哪些质子化状态对其生物活性负责。首先，我们使用1H NMR和13C NMR光谱实验测定了氨曲南在0.8 - 7.0的pH范围内的pKa值。其次，我们对从经典分子动力学模拟中提取的快照进行了量子化学计算。在能量计算中使用了各种近似水平：用于几何弛豫的ONIOM(HF/3 - 21G*:AMBER)，用于电子和静电溶剂化能的B3LYP/6 - 31 + G**，以及用于吸引色散能的分子力学。将质子溶剂化自由能的值作为一个参数，并选择它以使小分子的计算pKa值与实验pKa值之间达到最佳匹配。总体而言，这种计算方案在药物分子的pKa计算中可以给出令人满意的结果。
