Conformational Change Initiates Dehydration in Fluconazole Monohydrate
Conformational Change Initiates Dehydration in Fluconazole Monohydrate
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DOI：
10.1021/acs.cgd.0c00768
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发表时间：
2020-09-02
影响因子：
3.8
通讯作者：
Cruz-Cabeza, Aurora J.
中科院分区：
文献类型：
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作者：
Basford, Patricia A.;Cameron, Christopher A.;Cruz-Cabeza, Aurora J.
实验和计算技术相结合监测了一水氟康唑(MH)的脱水过程，从而从分子水平上揭示了脱水机理。在实验上，观察到脱水在55℃左右开始，并在100℃左右完成，亚稳态Pbca，Z‘=1晶型(AH-C)是脱水的唯一产物(由原位热阶段PXRD确定)。构象和结构的变化被认为是脱水过程的启动和进展的关键。热膨胀沿c轴方向最为显著，分子动力学(MD)模拟和实验观察证实，水在垂直于该方向的平面内通过MH晶格迁移。发现水在(001)面内沿a轴和b轴方向均有迁移。分子动力学模拟表明，在室温下，水不能在晶格内迁移。在70摄氏度(343K)下迁移是可能的，但只有在羟基发生构象变化之后。羟基周围的构象变化是削弱MH结构中的氟康唑-水氢键和促进形成多晶型AH-C所需的氟康唑-氟康唑氢键的关键。
Experimental and computational techniques have been used in combination to monitor the dehydration process of fluconazole monohydrate (MH), thus unveiling the dehydration mechanism at the molecular level. Experimentally, dehydration was observed to start at around 55 degrees C and be complete around 100 degrees C, with the metastable Pbca, Z' = 1 polymorph (AH-C) as the sole product of dehydration (as determined by in situ hot-stage PXRD). Conformational and structural changes were identified as key in the initiation and progression of the dehydration process. Thermal expansion is most significant along the c axis, with molecular dynamics (MD) simulations and experimental observations identifying that water migrates through the MH crystal lattice within the plane perpendicular to that direction. Water was found to migrate within the (001) plane along both the a and b axis directions. The MD simulations revealed that water was not able to migrate within the lattice at room temperature. Migration at 70 degrees C (343 K) was plausible, but only after the hydroxyl group underwent a conformational change. The conformational change, around the hydroxyl group, is key to both the weakening of the fluconazole-water hydrogen bonding, found in the MH structure, and the promotion of the fluconazole-fluconazole hydrogen bonding, required for the formation of polymorph AH-C.