On March 28, the research paper titled "Flexible Scaffold-based Cheminformatics Approach for Polypharmacological Drug Design" was published online in Cell by the research group led by Professor Wang Sheng from the Center for Excellence in Molecular Cell Science at the Chinese Academy of Sciences, in collaboration with Professor Cheng Jianjun's team from the iHuman Institute at ShanghaiTech University and Professor Xu Huaqiang's team from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences. This study, which integrates chemical informatics, structural biology, cellular functional studies, and in vivo animal behavior research, introduces a groundbreaking concept called the "Flexible Scaffold-based Cheminformatics Approach" (FSCA) for multi-target, multi-functional drug design. This approach provides a new pathway for drug development aimed at treating complex psychiatric disorders.
Treating psychiatric disorders poses a significant challenge in the medical field due to their extremely complex etiology and diverse symptomatology. Conditions like schizophrenia and dementia, for instance, manifest not only with psychiatric disturbances but also cognitive impairments such as memory loss and confusion. Conventional single-target drugs often fail to meet patients' needs, while combination therapy presents risks of unknown side effects due to drug interactions within the body. Hence, there is an urgent need to develop drugs that can simultaneously target multiple receptors.
Taking serotonin 2A and 1A receptors as examples, these two receptors are major targets for many psychiatric drugs. For instance, clozapine, a selective antagonist of the serotonin 2A receptor, has shown clinical efficacy in alleviating psychiatric symptoms associated with schizophrenia, Alzheimer's disease, and Parkinson's disease, but it fails to slow down the progression of cognitive decline in patients. Additionally, agonists of the serotonin 1A receptor, such as tandospirone, can improve psychiatric symptoms in elderly dementia patients. In the treatment of schizophrenia, tandospirone, when combined with typical antipsychotic drugs like haloperidol, can improve both psychiatric disturbances and some cognitive functions simultaneously. Therefore, the research team attempted to design multi-target, bidirectional active compound molecules that act on both types of receptors to achieve bidirectional regulation of psychiatric disease symptoms.
Multi-target drug molecules can undergo conformational changes when binding to different types of receptors, allowing for the adjustment of molecular conformation and binding poses to adapt to the shapes of different receptor pockets, thereby modulating receptor activity.
Based on years of research on receptor structure pharmacology, the research team found that agonist ligands of the serotonin receptor family tend to adopt an "extended-up" binding state, while antagonist ligands tend to adopt a "bent-down" binding state. Representative agonists and antagonists include the hallucinogen LSD and the antipsychotic drug loxapine, respectively. The tetracyclic scaffold of LSD presents an approximately planar conformation in the receptor, while the side chain diethylamide group extends upward, binding to a shallow pocket on the receptor; in contrast, the tetracyclic scaffold of loxapine presents a bent conformation in the receptor, with the connected butyrophenone fluorophenyl group slanting downward, binding to a deep pocket on the receptor. Studies have shown that drugs with similar structures exhibit predictable binding modes to receptors. Inspired by this concept, researchers used cheminformatics methods to screen for multi-ring scaffolds with variable conformations in two compound libraries, ChEMBL and Enamine, and connected them with a second pharmacophore, fluorophenyl ring, enabling the complete molecule to adopt both "extended-up" and "bent-down" conformations when binding to serotonin 1A and 2A receptors, respectively, thus achieving bidirectional activity of activating serotonin 1A receptor and antagonizing serotonin 2A receptor. To validate this concept, the researchers selected a representative tetracyclic scaffold connected to a fluorophenyl group, synthesized IHCH-7179, and verified its multiple pharmacological properties through cellular functional experiments, complex structure analysis, and behavioral pharmacology from multiple perspectives.
This study identifies the characteristics that a universal flexible scaffold should possess and proposes a novel approach for designing multi-target, multi-functional drugs. It deepens scientists' understanding of pharmacotherapy for complex psychiatric disorders and provides theoretical guidance for the future development of more effective multi-target drugs targeting complex diseases.
The research was supported by the National Natural Science Foundation of China, the National Key Research and Development Program, the Natural Science Foundation of Shanghai, and the Youth Innovation Promotion Association, Chinese Academy of Sciences.
Link to the paper
(A) The design concept of multi-target, multi-effect active drug precursors represented by IHCH-7179 and their potential applications in the treatment of schizophrenia and dementia; (B) Screening of multi-ring skeletal compounds with variable conformational features using chemoinformatics methods in the ChEMBL and Enamine compound libraries.
