Virtual cocrystal screening

Calculated gas phase molecular electrostatic potential surfaces have been used to identify sets of H-bond donor and H-bond acceptor sites that describe the possible intermolecular interaction sites on the surface of a molecule. The calculated H-bond parameters, alpha(i) and beta(j), were used to estimate interaction site pairing energies in the solid form of the compound through a hierarchical mapping of complementary donor and acceptor sites: the interaction energy for each contact is simply given by the product -alpha(i)beta(j). The approach assumes that all of the interactions that can be made in the solid are made and that the details of three-dimensional structure and crystal packing are of secondary importance. Comparison of the energy of two pure solids with cocrystals of various stoichiometries gives an energy difference, Delta E, which is a measure of the probability of forming a cocrystal. Tests on an experimental cocrystal screen from the literature and the recall of coformers for caffeine and for carbamazepine from a list of nearly 1,000 candidates have been used to validate the utility of the method. For systems that are experimentally found to form cocrystals, the calculated energy parameter Delta E tends to be very favourable. In the best case, for 846 potential caffeine coformers from the EAFUS list, 80% of the experimentally observed hits are in the top 11% of the ranked list of Delta E values. The results provide a calibration between the value of Delta E and the probability of cocrystal formation: when the cocrystal is favored by more than 11 kJ mol(-1) over the two pure solids, the probability of obtaining a cocrystal is better than 50%. An advantage of this approach is that it is sufficiently fast to be used as a high throughput virtual screening tool.