Researchers have discovered a way to be able to design efficient medicines by giving the compound a correct 3D orientation which is important for its biological activity
Advancement in healthcare is dependent upon understanding the biology of a disease, developing techniques and medicines for correct diagnosis and finally, treatment of the disease. After many decades of research scientists have gained an understanding of complex mechanisms which are involved in a particular disease which has led to many novel discoveries. But there are still several challenges that we face when it comes to finding and developing a new drug which would offer a novel way of treatment. We still have no medicines or methods to combat many diseases. The journey from first discovering a potential drug and developing it is not only complex, time-consuming and expensive but sometimes even after years of study there are poor outcomes and all hard work goes in vain. Structure-based drug design is now a potential area in which success has been achieved for new drugs. This has been possible because of massive and growing genomic, proteomic and structural information available for humans. This information has made it possible to identify new targets and investigate interactions between the drugs and their targets for drug discovery. X-ray crystallography and bioinformatics have enabled wealth of structural information on drug targets. Despite this progress, a significant challenge in drug discovery is the ability to control the three-dimensional (3D) structure of molecules – the potential drugs - with minute precision. Such constraints are a severe limitation to discovering new drugs.
In a breakthrough study published in Science, a team led by researchers at Graduate Centre of The City University of New York have devised a way which makes it possible to alter 3D structure of chemical molecules faster and more reliably during the drug discovery process. The team has built upon the work of Noble laureate Akira Suzuki, a chemist who developed cross-coupling reactions which showed that two carbon atoms can be bonded using palladium catalysts and won the Noble Prize for this particular work. His original discovery enabled researchers to construct and synthesize new drug candidates faster but it was limited to only making flat 2D molecules. These novel molecules have been successfully used for applications in medicine or industry but Suzuki’s method could not be used to manipulate a molecule’s 3D structure during the design and development process of a new drug. Most biological compounds used in medical field are chiral molecules. Which means two molecules are mirror images of each other though they may have the same 2D structure - like a right and left hand. Such mirror molecules will have different biological effect and response in the body. One mirror image could be medically beneficial while the other could have an adverse effect. A prime example of this is the thalidomide tragedy in the 1950s and 1960s when drug thalidomide was prescribed to pregnant women as a sedative in the form of both its mirror images, one mirror image was useful but the other caused devastating birth defects in the babies born to those women who consumed the wrong drug. This scenario imparts significance to controlling the alignment of individual atoms which constitute a molecule’s 3D structure. Though Suzuki’s cross-coupling reactions are used routinely in drug discovery, the gap is yet to be filled in manipulating 3D structure of molecules.
This study was aimed at achieving control which would help in selectively forming the mirror images of a molecule. Researchers designed a method to carefully orient the molecules within their 3D structures. They first developed statistical methods which predict outcome of a chemical process. Then these models were applied to develop suitable conditions in which 3D molecular structure could be controlled. During palladium-catalysed cross-coupling reaction different phosphine additives are added which influence the final 3D geometry of the cross-coupling product and understanding this process was crucial. The ultimate aim was to either preserve the 3D orientation of the starting molecule or invert it to produce its mirror image. The methodology should ‘selectively’ either retain or invert the geometry of the molecule.
This technique can help researchers create libraries of structurally diverse novel compounds while being in a position to control the 3D structure or architecture of these compounds. This will enable faster and efficient discovery and design of new drugs and medicines. Structure-based drug discovery and design has untapped potential which can be utilized to discover new drugs. Once a drug is discovered there is still a long way to go from the laboratory to animal trials and finally human clinical trials only after which the drug is available in the market. Current study provides a strong foundation and an apt starting point to the drug discovery process.
Shibin Zhao et al. 2018, ‘Enantiodivergent Pd-catalyzed C–C bond formation enabled through ligand parameterization’, Science, DOI: https://doi.org/10.1126/science.aat2299