Cocrystal diversity

L. Orola, M.V. Veidis, Nicotinamide fumaric acid supramolecular cocrystals diversity of stoichiometry, CrystEngComm 11 (2009) 415-417. 

Compared with monocyclic piperazine scaffolds, bicyclic piperazines often provide platforms with even more points of diversity compared to monocyclic piperazines. Condensed bicyclic piperazines enlarge the chemical space of piperazine scaffolds, as well as the family of target proteins. For example, bicyclic piperazinones were prepared and evaluated in vitro and in vivo as thrombin inhibitors [49]. The cocrystal structure of a bicyclic piperazinone inhibitor 154 with thrombin was shown in Fig. 9. So far, chemists have developed many MCR methods to synthesize a variety of bicyclic piperazine scaffolds. 

Interestingly, in the same work [23] Etter and Adsmond reported two polymorphs of a 1 1 cocrystal containing 25 and malonic acid 27. Both crystallised from solution, but only one was obtainable from solid-state grinding. Contrary to the examples mentioned above, this instance suggests that solution crystallisation may at times offer more product diversity than grinding. 

G.P. Stahly, Diversity in single- and multiple-component crystals the search for and prevalence of polymorphs and cocrystals, Cryst. Growth Des. 7 (2007) 1007-1026. 

A.V. Trask, J. van de Streek, W.D.S. Motherwell, W. Jones, Achieving polymorphic and stoichiometric diversity in cocrystal formation importance of solid-state grinding, powder X-ray structure determination, and seeding, Cryst. Growth Des. 5 (2005) 2233-2241. 

Thus, the solid phase synthesis of a peptide library led to a diverse set of RabGGTase inhibitors with moderate inhibition of prenylation in cells. These results show that the flexible peptide backbone is probably not suitable for a structure-guided inhibitor approach or SAR analysis due to different binding modes adopted by the peptides. However, the structural insights obtained from the inhibitor-RabGGTase cocrystal structures provided crucial information that was used for the development of other potent and specific RabGGTase inhibitors. 

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