iHuman Makes Progress in Polypharmacological Drug Development

Polypharmacology is the next generation of disease treatment, promising more effective drugs that are less toxic and have fewer side effects. However, polypharmacological drugs, which simultaneously act on multiple targets, remain extremely difficult to develop, though maybe not for long, according to a study published this week in Cell.

Apparently, the key lies in obtaining a better understanding of the three-dimensional structure of receptor proteins, and this week an international team of scientists led by ShanghaiTech University’s iHuman Institute published results showing the high-resolution atomic structure of the human serotonin receptor 2C (5-HT_2C); an important G-protein-coupled receptor (GPCR) drug target for the treatment of schizophrenia and drug abuse, and recently was central to the development of the anti-obesity drug Belviq®. 

Lead author Peng Yao said of their results, “This is an important step towards realizing the full potential of polypharmaceuticals. The ability to observe atomic-level structures of receptors like 5-HT_2C will revolutionize drug development.”

Together with partners from University of North Carolina, University of Southern California and University of Copenhagen,three-dimensional structural images of 5-HT_2C were presented in active and inactive states, and the structural basis of GPCR polypharmacology was deciphered. Such detailed data of key receptors will help drug hunters design new polypharmacology drugs, revolutionizing the treatment of disease.

"The detailed molecular structure of the 5-HT_2C receptor will help researchers understand the molecular basis of how polypharmacology and selectivity are achieved. This is the first step towards a rational utilization of the knowledge for future GPCR drug design,” said corresponding author and iHuman Executive Director, Professor Liu Zhijie.

iHuman Founding Director and co-author Professor Raymond Stevens added “Our hope is that our approach will be invaluable for determining the polypharmacological determinants of other promiscuous drugs, and provide a roadmap for the rational design of polypharmacological ligands to treat some of the most challenging diseases, particularly those in mental health.”

Polypharmacology stands in stark contrast to traditional therapeutic drugs which have, for the past several decades, been designed for a single target to avoid unwanted, off-target side-effects. However, the one drug-one target strategy is nonetheless frequently unsuccessful and struggles to treat complex central nervous system (CNS) disorders where the etiologies may be multifactorial and polygenic. Drugs with a polypharmacological basis can be more effective therapeutics, as exemplified by the atypical antipsychotics clozapine (Clozaril®) and aripiprazole (Abilify®), which interact with numerous GPCRs. As we start to develop a more complete picture of the human genome and proteome, polypharmecutical approaches will likely become more powerful. 

This work was supported by the Shanghai Municipal Government; ShanghaiTech University; the grants from the Ministry of Science and Technology of China (2014CB910400 and 2015CB910104); the National Nature Science Foundation of China (31330019) (to Liu Zhijie); the NIH (R01MH112205 and U19MH82441 to Bryan Roth; U54GM094618 to Vsevolod Katritch); the Russian Science Foundation (16-14-10273 to Petr Popov); and Lundbeck Foundation (R163-2013-16327 to David E. Gloriam).

Read more at: http://www.cell.com/cell/fulltext/S0092-8674(18)30001-1

About the iHuman Institute ( http://ihuman.shanghaitech.edu.cn)

Located in the heart of Zhangjiang High Technology Park in Shanghai, China, the iHuman Institute at ShanghaiTech University is the Asian gateway to the world for imaging across the scales.  The iHuman Institute is focused on the basic and applied science of building an atomic resolution 3-dimensional model of the human body.  By integrating molecular, cellular and organ imaging together, we can understand how all the parts work together to make us who we are.  One of iHuman Institute’s dreams is to see routine and robust whole body imaging occur at the atomic resolution to detect diseases before it is too late to treat with medicines.  

A: 3D structures of 5-HT_2C receptor at different activation states, activated structure is in orange color, inhibited structure is in green color. B: The structural difference of extracellular portions of the receptor. C: The structural difference of intracellular portions of the receptor.

The iHuman research team (taken at the multimedia center of ShanghaiTech University)