This study is a part of the extensive research intending to provide the structural insights on somatostatin and its receptor. Herein, we have studied the structural complexity involved in the binding of somatostatin receptor 2 (SSTR2) with its agonists and antagonist. A 3D QSAR study based on comparative molecular field analysis and comparative molecular similarity analysis (CoMSIA) discerned that a SSTR2 ligand with electronegative, less-bulkier, and hydrogen atom donating/accepting substitutions is important for their biological activity. A conceptual density functional theory (DFT) study was followed to study the chemical behavior of the ligands based on the molecular descriptors derived using the Fukui's molecular orbital theory. We have performed molecular dynamics simulations of receptor-ligand complexes for 100 ns to analyze the dynamic stability of the backbone Cα atoms of the receptor and strength and approachability of the receptor-ligand complex. The findings of this study could be efficacious in the further studies understanding intricate structural features of the somatostatin receptors and in discovering novel subtype-specific ligands with higher affinity. Communicated by Ramaswamy H. Sarma.

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Somatostatin receptor 1 (SSTR1), a subtype of somatostatin receptors, is involved in various signaling mechanisms in different parts of the human body. Like most of the G-protein-coupled receptors (GPCRs), the available information on the structural features of SSTR1 responsible for the biological activity is scarce. In this study, we report a molecular-level understanding of SSTR1–ligand binding, which could be helpful in solving the structural complexities involved in SSTR1 functioning. Based on a three-dimensional quantitative structure–activity relationship (3D-QSAR) study using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA), we have identified that an electronegative, less-bulkier, and hydrophobic atom substitution can substantially increase the biological activity of SSTR1 ligands. A density functional theory (DFT) study has been followed to study the electron-related properties of the SSTR1 ligands and to validate the results obtained via the 3D-QSAR study. 3D models of SSTR1–ligand systems have been embedded in lipid–lipid bilayer membranes to perform molecular dynamics (MD) simulations. Analysis of the MD trajectories reveals important information about the crucial residues involved in SSTR1–ligand binding and various conformational changes in the protein that occur after ligand binding. Additionally, we have identified the probable ligand-binding site of SSTR1 and validated it using MD. We have also studied the favorable conditions that are essential for forming the most stable and lowest-energy bioactive conformation of the ligands inside the binding site. The results of the study could be useful in constructing more potent and novel SSTR1 antagonists and agonists.

We report on SSTR5 receptor modeling and its interaction with reported antagonist and agonist molecules. Modeling of the SSTR5 receptor was carried out using multiple templates with the aim of improving the precision of the generated models. The selective SSTR5 antagonists, agonists and native somatostatin SRIF-14 were employed to propose the binding site of SSTR5 and to identify the critical residues involved in the interaction of the receptor with other molecules. Residues Q2.63, D3.32, Q3.36, C186, Y7.34 and Y7.42 were found to be highly significant for their strong interaction with the receptor. SSTR5 antagonists were utilized to perform a 3D quantitative structure-activity relationship study. A comparative molecular field analysis (CoMFA) was conducted using two different alignment schemes, namely the ligand-based and receptor-based alignment methods. The best statistical results were obtained for ligand-based ([Formula: see text], [Formula: see text] = 0.988, noc = 4) and receptor-guided methods (docked mode 1:[Formula: see text], [Formula: see text], noc = 5), (docked mode 2:[Formula: see text] = 0.555, [Formula: see text], noc = 5). Based on CoMFA contour maps, an electropositive substitution at [Formula: see text], [Formula: see text] and [Formula: see text] position and bulky group at [Formula: see text] position are important in enhancing molecular activity.