Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, Leninskii prosp. 31, 119991 Moscow, Russia.
Faculty of Natural Science, Mendeleev University of Chemical Technology, Miusskaya Square 9, 125047 Moscow, Russia.
Int J Mol Sci. 2022 Jun 4;23(11):6302. doi: 10.3390/ijms23116302.
The study of the formation of microstructures during the interaction of a protonated drug-like compound (API) with a maleic acid monoanion sheds light on the assembly processes in an aqueous solution at the molecular level. Molecular dynamics (MD) simulations coupled with density functional theory (DFT) calculations made it possible to find initial hydrogen bonding motifs during the assembly process, leading to the formation of heterodimers and trimers. The process of trimer formation [protonated API-maleic acid monoanion-protonated API] proceeds through the formation of three intermolecular H-bonds by the CO group of the maleic acid monoanion in both systems. The total enthalpy/energy of these H-bonds is more than 70 kJ/mol. Thus, the maleic acid monoanion plays a key role in the processes of association in aqueous solution, and the interaction of the maleic acid monoanion with API is more preferable than the interaction of API molecules with each other. DFT computations in the discrete continuum approximation reveal the spectral features of heterodimers and trimers, and the ATR-IR spectra confirmed these findings. MD simulations followed by DFT calculations made it possible to describe the initial stages of the formation of pharmaceutical cocrystals in an aqueous solution.
质子化类似药物化合物 (API) 与马来酸单阴离子相互作用过程中微观结构的形成研究，揭示了水溶液中分子水平的组装过程。分子动力学 (MD) 模拟与密度泛函理论 (DFT) 计算相结合，使得在组装过程中找到初始氢键模式成为可能，从而形成杂二聚体和三聚体。三聚体形成过程 [质子化 API-马来酸单阴离子-质子化 API] 在两个体系中均通过马来酸单阴离子的 CO 基团形成三个分子间氢键进行。这些氢键的总焓/能量超过 70 kJ/mol。因此，马来酸单阴离子在水溶液中的缔合过程中起着关键作用，马来酸单阴离子与 API 的相互作用比 API 分子之间的相互作用更有利。离散连续近似的 DFT 计算揭示了杂二聚体和三聚体的光谱特征，ATR-IR 光谱证实了这些发现。MD 模拟随后的 DFT 计算使得在水溶液中描述药物共晶形成的初始阶段成为可能。
