Major depression is the most common mental disorder that negatively affects the social, occupational, and educational aspects of people's lives and is one of the leading causes of disability worldwide (Chen et al., 2021; Mathers and Loncar, 2006). Unfortunately, the COVID-19 pandemic has exacerbated the incidence of major depression in recent years and poses a challenge to global mental healthcare (Hampshire et al., 2021; Ren et al., 2022). Selective monoamine uptake inhibitors are widely used as the main treatment for depression (Li, 2020; Nemeroff, 1998; Ren et al., 2022); however, these marketed drugs have varying degrees in delayed onset of action (4–6 w), relatively low effectiveness (50–70%), and a series of side effects, including sexual dysfunction, cognitive impairment, and suicidal tendency etc. (Li, 2020). It is imperative to develop novel compounds with a quicker onset of action and low toxicity to meet the major clinical need (Sun et al., 2022), since current treatments also do not achieve full remission of depression symptoms.

Recently, sigma receptors have gained popularity due to their chaperone function, which exerts a broad spectrum of biological functions (Salaciak and Pytka, 2022). The sigma receptor family consists of two main family members, sigma-1 (σ-1) and sigma-2 (σ-2) receptors, that are classified according to their pharmacological profiles (Quirion et al., 1992; Schmidt and Kruse, 2019). σ-1 receptors, a type of chaperonin protein, are mainly located in the cholesterol-rich region of the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAM) (Hayashi and Su, 2007; Su et al., 2010). It acts as a chaperone protein with translocation properties and modulates several essential cellular processes, such as neurotransmitter release, inflammation, cell survival, autophagy, and synaptogenesis (Hayashi and Su, 2007). The σ-1 receptor has attracted increasing attention due to its ability to interact with and regulate a wide range of other proteins, ion channels, and receptors, directly or indirectly (Prasanth et al., 2021). These interactions occur within central nervous system (CNS) disorders, and several σ-1 receptor ligands have been developed to target neurodegenerative diseases (Ren et al., 2022; Salaciak and Pytka, 2022; Ye et al., 2020), including Alzheimer's, Parkinson's, and Huntington's disease, mental disorders, and cognitive deficits. To our knowledge, there are several reports that have suggested that σ-1 receptor selective agonists have potential rapid onset and antidepressant activities (Fishback et al., 2010; Lucas et al., 2008; Skuza and Rogoz, 2002). Additionally, it was recently determined that the σ-2 receptor, also termed the transmembrane protein 97 (TMEM97), is a transmembrane protein found in the ER that regulates the NPC intracellular cholesterol transporter 1 (NPC1) (Alon et al., 2017). The current prevailing view suggests that σ-2 receptors are not only associated with tumor proliferation but also play an important role in cell survival (Abbas et al., 2020) and are involved in the pathogenesis of neurological disorders (Guo and Zhen, 2015). Therefore, development of new drugs targeting sigma receptors for the treatment of neuropsychiatric disorders holds good promise.

YL-0919 [(1-(1-benzyl-4-hydroxypiperidin-4-ylmethyl)-2(1H)-pyridinone hydrochloride] (Fig. 1A), a novel compound developed in our laboratory, acts as a selective 5-HT reuptake inhibitor (SSRI) and partial 5-HT1A receptor agonist and exhibits fast-onset anti-depressant effects (within 3–7 days) in rodent and primate animal depressive models (Ran et al., 2018; Sun et al., 2019; Yin et al., 2020; Zhang et al., 2022). YL-0919 is currently being used in a phase II clinical trial (Cui et al., 2019). Although the pharmacological profile of YL-0919 has been widely reported, elucidation of its potential neural mechanisms remains limited. In particular, recent studies have found that YL-0919 has a fast-onset antidepressant effect without increasing suicidal tendencies and causing weight gain. However, the available pharmacological targets of YL-0919 cannot fully explain these results from preclinical or clinical studies. Therefore, there is a continuous need to further explore the possible pharmacological targets of YL-0919.

Machine learning-based target fishing models have become popular over the last few years due to the increased availability of bioactivity data (Cockroft et al., 2019), and structure-based molecular docking virtual screening is increasingly becoming a powerful tool for the discovery of new compounds, as it is faster and more economical than experimental screening (Bajad et al., 2021; Kumari et al., 2021). In the present work, the YL-0919 chemical structure was used as input for STarFish and results suggested that the σ-1 receptor may be the potential protein target of YL-0919 (Supplementary Fig. 1). Virtual molecular docking and further radioreceptor ligand binding assays were implemented to identify the affinity of YL-0919 for the sigma-1 and sigma-2 receptors. Results showed that YL-0919 bound the sigma-1 receptor with greater affinity than the sigma-2 receptor. Based on previous research paradigms (Hayashi and Su, 2007), YL-0919 was first identified based on its agonistic or antagonistic interactions with positive tool compounds in vitro (Gaja-Capdevila et al., 2022). The antidepressant effects of YL-0919 were then evaluated in vivo. Collectively, it was concluded that the novel compound, YL-0919, acts as a σ-1 receptor agonist and is a putative antidepressant drug candidate with fast-onset effects.