(219a) Addressing Density Functional Theory Modeling Challenges in the Crystals of Highly-Flexible Pharmaceuticals

Density functional theory modeling has transformed crystal structure prediction in recent years, and crystal structures of rigid and moderately flexible molecules can be now routinely be predicted accurately. However, significant challenges remain for highly-flexible molecules such as drugs, as will be demonstrated by presenting the contrasting results for molecules XXXI and XXXII from the 7th Blind Test of Crystal Structure Prediction. Whereas moderately flexible molecule XXXI represents a relatively straightforward example for crystal structure prediction, the highly flexible drug molecule XXXII proves extremely challenging. Even obtaining reliable conformational energies for molecule XXXII proves very difficult. General computational strategies for how to handle such challenging cases will be discussed.