Molecular-Level Understanding of the Somatostatin Receptor 1 (SSTR1)-Ligand Binding: A Structural Biology Study Based on Computational Methods.

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.