Day G M, S Motherwell W D, Jones W
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK.
Phys Chem Chem Phys. 2007 Apr 14;9(14):1693-704. doi: 10.1039/b612190j. Epub 2007 Jan 24.
A computational exploration of the low energy crystal structures of the pharmaceutical molecule phenobarbital is presented as a test of an approach for the crystal structure prediction of flexible molecules. Traditional transferable force field methods of modelling flexible molecules are unreliable for the level of accuracy required in crystal structure prediction and we outline a strategy for improving the evaluation of relative energies of large sets of crystal structures. The approach involves treating the molecule as a set of linked rigid units, whose conformational energy is expressed as a function of the relative orientations of the rigid groups. The conformational energy is calculated by electronic structure methods and the intermolecular interactions using an atomic multipole description of electrostatics. A key consideration in our approach is the scalability to more typical pharmaceutical molecules of higher molecular weight with many more atoms and degrees of flexibility. Based on our calculations, crystal structures are proposed for the as-yet uncharacterised forms IV and V, as well as further polymorphs of phenobarbital.
本文展示了对药物分子苯巴比妥低能晶体结构的计算探索，以此作为一种预测柔性分子晶体结构方法的测试。传统的用于模拟柔性分子的可转移力场方法对于晶体结构预测所需的精度水平而言并不可靠，我们概述了一种用于改进对大量晶体结构相对能量评估的策略。该方法涉及将分子视为一组相连的刚性单元，其构象能量表示为刚性基团相对取向的函数。构象能量通过电子结构方法计算，分子间相互作用则使用原子多极静电描述。我们方法中的一个关键考量是对具有更多原子和更高柔性程度的更典型高分子量药物分子的可扩展性。基于我们的计算，提出了尚未表征的晶型IV和V以及苯巴比妥其他多晶型物的晶体结构。
