S2RSLDB: a comprehensive manually curated, internet-accessible database of the sigma-2 receptor selective ligands
Sigma (?) receptors are accepted as a particular receptor class consisting of two subtypes: sigma-1 (?1) and sigma-2 (?2). They are distinguished by molecular weight (MW), drug actions, pharmacological profiles and molecular characteristics [1, 2]. The ?1 receptor has a MW of 25.3 kDa and was first cloned from guinea pig liver (UniProtID Q60492, Gene names SIGMAR1, CHEMBL4153) in 1996 [3, 4], and afterwards from human placental choriocarcinoma cell (UniProtID Q99720, Gene names SIGMAR1, CHEMBL287) [5]. In addition, the ?1 receptor was also cloned by other organisms, like mouse (UniProtID O55242, CHEMBL3465), rat (UniProtID Q9R0C9, CHEMBL3602), brushtail possum (UniProtID Q5PXE2), ermine (UniProtID Q5PXE3), bovine (UniProtID Q58DH7), chicken (UniProtID Q5ZL84), and zebrafish (UniProtID Q7ZWG9). Recently the crystal structures of the human ?1 receptor in complex with two ligands, has been reported (PDB ID 5HK1 and 5HK2) [3, 6].
The ?2 receptor has not yet been cloned or crystallized and the knowledge about this receptor has mostly been generated through in vitro receptor radioligand binding studies [7, 8]. As reported the ?2 receptor has a MW between 18 and 21 kDa [9, 10]. It has been postulated that the ?2 receptor binding site may be located in the progesterone receptor membrane component 1 (PGRMC1), even if its MW (25 kDa) is different from that of ?2 receptor [10, 11].
The ?1 receptor is involved in aging and various diseases, like schizophrenia, depression, Alzheimer’s disease and ischemia. The ?1 receptor agonists have showed neuroprotective, anti-amnestic and antidepressant effects [12–14]. Conversely, ?1 receptor antagonists are considered antiproliferative, antiangiogenic and to have modulatory effects on opioid analgesia [15–17]. Some studies suggested that ?1 receptor is involved in modulating the synthesis and release of dopamine and also to act as a molecular chaperone at the mitochondrion-associated endoplasmic reticulum membrane (MAM) where it regulates calcium signaling between the two organelles [4, 18–20].
Despite the lack of structural information, the ?2 receptor has gained remarkable attention due to its involvement in several human diseases, including but not limited to depression, anxiety and cancer diagnosis and treatment [21–23]. The ?2 receptor ligands determine tumor cell death through apoptotic and non-apoptotic pathways, although their mechanisms of action have not been fully elucidated [24, 25]. In addition, the overexpression of ?2 receptor in several tumor cell lines is noteworthy [26–28]. The ?2 receptor is expressed about tenfold more in proliferating tumor cells compared with quiescent tumor cells, keeping the ?2 receptor ligands highly indicate for ligand-targeted cancer therapeutic strategies and as imaging agents [23, 29–32]. This peculiarity has been used for the development of ?2 receptor selective ligands as Positron Emission Tomography (PET) imaging tools. [18F]ISO-1, a promising PET ligand targeting ?2 receptor, has been evaluated in clinical trial for the assessment of cellular proliferation in tumors by PET and three additional phase I clinical trials on this compound are actually ongoing [33–36]. These differences in the pharmacological profiles of the ? receptor subtypes, prompt to a continue research of ligands that selectively target each of them. However, whilst several ligands selectively bind to the ?1 receptor or indistinctly to the two receptor subtypes, the development of compound endowed with high selectivity for the ?2 receptor has been challenging and in some cases occurred through an accidental discovery [23].
Due to the lack of structural information about the ?2 receptor and its growing implication in cancer diagnosis and treatment, a thorough and in-depth collection of the selective ?2 receptor ligands could result in a helpful tool for drug discovery. Herein, an online ligand database named sigma-2 Receptor Selective Ligands Database (S2RSLDB) based on 2D structural information, computed physicochemical properties, pharmacological properties together with the experimental procedure protocols, retrieved from the literature, has been built and resulted in more than 650 compounds. The database contains all the ligands that selectively bind the ?2 receptor (i.e. K
i ?1/?2 1). The S2RSLDB is freely available online without account login and having a powerful search engine the user may build complex queries, sort tabulated results, generate color coded 2D and 3D graphs and download the data for additional offline screening.
The collection here reported is extremely useful for the development of ligands endowed of ?2 receptor affinity, selectivity, and appropriate physicochemical properties. To the best of our knowledge, there is not any online database reporting such complete compounds map for this receptor. Moreover, in most cases these do not allow a comparison between the compound’s features and a complete and correct set of compounds is difficult to be returned. The database will be updated yearly and in the near future, an online submission form will be available to help with keeping the database widely spread in the research community and continually updated.