Crystal Structure Prediction of a Flexible Molecule of Pharmaceutical Interest with Unusual Polymorphic Behavior

Crystal structure prediction methods have been used to explore the potential energy landscape for crystals of a melatonin agonist (MA). All known experimental polymorphs were found in the search for crystal packing alternatives with a single molecule in the asymmetric unit, and the predicted order of stability agrees with experiment. The crystal structure corresponding to the global minimum has not been observed experimentally, but analysis of the crystal structures of similar molecules in the Cambridge Structural Database (CSD) indicates that the packing motif present in the predicted structure is also found in nature. To date it has not been experimentally possible to crystallize the most stable polymorph of the biologically active R-enantiomer, whereas the S-enantiomer readily crystallizes in the stable form. Analysis of the results shows that this polymorph has an uncommon packing motif which is found just once among the 12 lowest energy predicted structures but is seen in two crystal structures of MA-like molecules whose structures are stored in the CSD. On the basis of the calculations and comparisons with experimental crystal structures, suggestions are made as to possible routes for crystallizing the, as yet unknown, polymorph of MA, which corresponds to the predicted structure with the lowest lattice energy.本研究采用晶体结构预测方法，探索了褪黑素激动剂（melatonin agonist, MA）晶体的势能面。在不对称单元仅含单分子的晶体堆积候选结构搜索中，所有已知实验多晶型均被成功检索得到，且预测的稳定性排序与实验结果一致。对应全局能量极小值的晶体结构尚未被实验观测到，但通过对剑桥晶体结构数据库（Cambridge Structural Database, CSD）中同类分子晶体结构的分析可知，该预测结构中的堆积基元在自然界中同样存在。截至目前，实验上仍无法获得具有生物活性的R对映异构体的最稳定多晶型，而S对映异构体则可轻松以稳定晶型析出。结果分析表明，该多晶型拥有一种罕见的堆积基元：在12个低能量预测晶体结构中，该基元仅出现一次，但在剑桥晶体结构数据库收录的2个MA同类分子晶体结构里却存在该基元。基于本次计算结果与实验晶体结构的对比分析，本研究提出了潜在的结晶路径，以期获得目前尚未被实验发现的、对应最低晶格能预测结构的MA多晶型。