Validation of a Computational Cocrystal Prediction Tool: Comparison of Virtual and Experimental Cocrystal Screening Results

A virtual cocrystal screening method
based on calculated gas phase
molecular electrostatic potential surfaces (MEPS) of the individual
components has been validated using experimental cocrystal screens
reported in the literature. The noncovalent interactions of a molecule
with its environment are described by a discrete set of independent
surface site interaction points (SSIPs), whose properties can be calculated
from the ab initio MEPS. The stability of a crystal
is estimated based on pairing SSIPs such that the sum of the pairwise
interaction energies is optimized. This provides a means of calculating
the relative stability of a cocrystal compared with the pure components
without knowing anything about the three-dimensional structures of
the crystalline states. For a set of potential crystal coformers (CCF),
the difference between interaction site pairing energies of different
solid forms (ΔE) provides a method for ranking
CCFs based on the calculated probability of cocrystal formation. The
method was applied to cocrystal screens of 18 compounds that reported
both hits and misses, and in most cases, the virtual cocrystal screen
reproduces experimental results well. In lists of CCFs ranked by ΔE, the experimentally observed hits were significantly enriched
at the top, and this indicates that virtual screening is a promising
tool for focusing experimental efforts on the most promising CCF candidates.