Exploiting the potential of allostery in the 5-HT2A receptor as a new paradigm for schizophrenia treatments

点击翻译按钮获取中文摘要

Schizophrenia is a chronic mental illness that affects approximately 1% of the world population and lowers the life expectancy of patients. The disease is manifested through positive, negative, and cognitive deficits. Antipsychotic drugs are the centerpiece of the treatment. They mainly target the aminergic receptor subfamily that belongs to the Class A of G protein-coupled receptors. Typical antipsychotics were dopamine D2 receptor (D2R) antagonists and are characterized by serious limitations. However, atypical medications partially antagonize the D2R and other aminergic receptors, mainly the serotonin 5-HT2A receptor (5-HT2AR). They perform better in alleviating the negative symptoms and cognitive deficits and are under intense investigation. This has made the 5-HT2AR one of the main target receptors for antipsychotic drugs. Despite the advantages of atypical antipsychotic treatments, schizophrenic patients still suffer from various positive, negative, cognitive symptoms and side effects. Thus, effective treatments for schizophrenia (improved profile of side effects, covering the majority of patients and symptoms of the disease) are still a monumental challenge. The problem, at least partially, roots in polypharmacology– the ability of one molecule to bind and activate multiple targets through which antipsychotics cause imbalances in the neurotransmitter pathways and unfavorable and non-selective regulation. Due to the high sequence and structure similarity shared among the orthosteric binding pocket of aminergic receptors, finding more selective medications is very challenging. Hence, new drug discovery paradigms should be explored. One such strategy, which is the focus of this study, is to find target-selective allosteric modulators for the 5-HT2AR and thus fine-tune the effect of the orthosteric ligands. Such allosteric modulators, when used together with known antipsychotics, can make the response more selective to the desired targets. Here, our main objective is to find target-selective negative allosteric modulators of the 5-HT2AR that can be used together with antipsychotic medications to fine-tune their effect. We will combine computational and experimental methods. The overall workflow to pursue this objective will be to 1) investigate potential allosteric pockets of the 5-HT2AR, 2) perform high-throughput virtual screening, 3) test the target selectivity of the selected compounds in cell-based assays and validate their pocket, 4) harness chemical space to find more negative allosteric modulators and understand what drives binding, and 5) establish a structure-activity relationship in order to optimize the hits and design final allosteric ligands.