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.