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.