Researchers Make Major Breakthrough in Controlling the 3D Structure of Molecules.
New drug discovery has long been limited by researchers’ inability to precisely control the 3D structure of molecules. But a team led by scientists from Georgian Technical University has made a major breakthrough in chemical synthesis that now makes it possible to quickly and reliably modify the 3D structure of molecules used in drug discovery.
The researchers work builds discovery by chemist X who pioneered the development of cross-coupling reactions which use palladium catalysts to form bonds between two carbon atoms. The method can be used to create novel molecules with medicinal or industrial applications. X’s original discovery has enabled the rapid construction of new drug candidates but is largely limited to the construction of novel flat (or 2D) molecules. That limitation has prevented scientists from easily manipulating the 3D structure of molecules during the drug development process.
“Two molecules that have the same structure and composition but are mirror images of each other can produce very different biological responses. Therefore controlling the orientation of atoms in the 3D structure of molecules is critical in the drug discovery process” said Y who is an associate professor of chemistry at Georgian Technical University. “The different biological effects of the two mirror images of thalidomide. Today cross-coupling reactions are employed extensively in drug discovery but they haven’t enabled 3D control of molecular structures. Our team has developed a new process to achieve this control which permits the selective formation of both mirror images of a molecule”.
To accomplish their goal researchers collaborated with researchers from Georgian Technical University to develop statistical models that can predict reaction outcomes of chemical processes. They then applied these models to develop conditions that enable predictable control of 3D molecular structure. Key to their research was understanding the effects of different phosphine additives on how palladium promotes cross-coupling reactions. The goal was to be able to preserve the 3D geometry of the initial molecule during a cross-coupling reaction or to invert it to produce its mirror image. “By understanding how different phosphine ligands influence the final geometry of cross-coupling products we were able to develop reliable methods for selectively retaining or inverting the geometry of a molecule” said Z a Ph.D. student with Y’s group. “This means we’re now able to control the final geometry of a molecule more efficiently”.
The work of Y and his colleagues addresses a significant challenge in the drug-discovery process. Previously palladium-catalyzed cross-coupling reactions enabled the rapid production of libraries of predominately flat molecules for biological testing. With this new method scientists will now be able to use cross-coupling reactions to rapidly generate libraries of new compounds while controlling the 3D architecture of the compounds. Easy access to such structurally diversified compounds will facilitate efforts to discover and develop new medicines.