The treatment of mental disorders has always been a major challenge in the medical field. The pathogenesis of these diseases is extremely complex, and the symptoms vary greatly. Take schizophrenia and dementia as examples, these two types of psychiatric patients exhibit not only mental confusion but also cognitive impairments such as memory loss and disordered thinking.
Traditional single-target drugs often fall short in meeting the comprehensive needs of patients, while combination therapy brings the risk of unforeseen side effects due to drug-drug interactions. Therefore, developing drugs that can target multiple receptors simultaneously is imperative. However, designing such multi-target, multi-effect drugs has remained a major challenge.
In a recent study published in Cell, a research team led by Prof. WANG Sheng from the CAS Center for Excellence in Molecular Cell Science, along with Prof. CHENG Jianjun from the iHuman Institute at ShanghaiTech University and Prof. Eric. H. Xu from the Shanghai Institute of Materia Medica, introduced a new concept of drug design named "Flexible Scaffold-based Cheminformatics Approach (FSCA)", which targets multiple receptors and has multiple effects, providing a new path for drug development to treat complex mental disorders.
To overcome the limitations of single-target therapies, the research team aimed to design multi-target, bidirectional active compound molecules capable of modulating both receptors. Specifically, they aimed to antagonize the serotonin 2A receptor while activating the serotonin 1A receptor, thereby achieving bidirectional regulation of symptoms associated with mental disorders. The rationale behind targeting serotonin receptors 1A (5-HT1AR) and 2A (5-HT2AR) stemmed from their validated efficacy in improving both psychotic and cognitive symptoms linked to neuropsychiatric disorders like schizophrenia and dementia.
"In the Northern Ocean, there is a fish named Kun... It turns into a bird named Peng." Drawing inspiration from Zhuangzi's metaphorical depiction of transformation in nature, wherein the fish Kun turns into the bird Peng, the researchers envisioned multi-target drug molecules undergoing morphological transformations when binding to receptors of different types. By adjusting the conformational states and binding poses of the molecules themselves, they aimed to adapt to the shapes of different receptor pockets and regulate receptor activity.
The study utilized a cheminformatics approach to identify conformation-flexible scaffolds from chemical databases ChEMBL and Enamine. The common features of these multicyclic scaffolds include 1) the first ring to be an aromatic ring or indole ring, 2) the second ring to be a non-aromatic ring that contains a sp3 hybridized nitrogen atom, 3) the third ring to have a protonated nitrogen atom suitable for fragment linking and salt bridging with the conserved amino acid D3.32 in aminergic receptors, 4) the conformational flexibility conferred by the C-N bond connecting the second and third rings. IHCH-7179, chemically synthesized via combing the identified aza-ergoline ring with the 4-fluorophenyl group was applied to validate the proposed FSCA method. The following docking and structural studies verified the predicted binding poses of IHCH-7179 at 5-HT1AR, 5-HT2AR, and receptors alike. IHCH-7179 also exhibited in vivo pharmacological efficacies in related rodent psychotic and cognitive models.
This study exemplifies a polypharmacology drug discovery process by integrating interdisciplinary methodologies. The validated pharmacological efficacies of IHCH-7179 hold great potential for its development as a therapeutic agent for schizophrenia and dementia-related psychosis. The FSCA approach introduced in this study may also serve as a valuable tool for identifying polypharmacological drugs and guiding their rational design.
Contact: wangsheng@sibcb.ac.cn
Reference: https://www.cell.com/cell/abstract/S0092-8674(24)00237-X
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