Researchers Develop Novel Method for Controlling 3D Structure of Molecules


Researchers from The Graduate Center of The City University of New York (GC/CUNY) created a new approach that quickly and reliably modifies 3D structure of molecules used in drug discovery

Akira Suzuki jointly won the Nobel Prize in Chemistry in 2010 for his work in development of cross-coupling reactions using palladium catalysts to form bonds between two carbon atoms. These cross–linking reactions can be used to create novel molecules with medicinal or industrial applications. Although, the discovery allowed rapid construction of novel drug candidates, it is limited to the construction of 2D molecules. Now, a research at the Advanced Science Research Center of GC/CUNY, created a new approach that quickly and reliably modifies 3D structure of molecules used in drug discovery. The research was published in the journal Science on September 20, 2018.

To develop statistical models that can predict reaction outcomes of chemical processes, the GC/CUNY researchers collaborated with researchers from The University of Utah. The resulting models were utilized to develop conditions that allow predictable control of 3D molecular structure. The team focused on understanding the effects of different phosphine additives and the mechanism of palladium in promoting cross-coupling reactions. Moreover, the researchers focused on preserving the 3D geometry of the initial molecule during a cross-coupling reaction, or to invert it to produce its mirror image. The team developed reliable methods for selectively retaining or inverting the geometry of a molecule by understanding the mechanism of phosphine ligands’ influence on the final geometry of cross-coupling products. This enabled the team to efficiently control the final geometry of a molecule.

The research was led by Mark Biscoe, research project director and an associate professor of chemistry with GC/CUNY and The City College of New York. The research reports a significant challenge in the drug-discovery process. Prior to this research, palladium-catalyzed cross-coupling reactions allowed rapid production of libraries of predominately flat molecules for biological testing. Now, the novel approach controls the 3D architecture of the compounds and enables to use cross-coupling reactions to rapidly generate libraries of new compounds. The findings are expected to facilitate efforts to discover and develop new medicines.