In the past two decades, the structural biology studies on G-protein coupled receptors (GPCRs) are on the rise. Understanding the relation between the structure and function of GPCRs is important as they play a huge role in various signaling mechanisms in a eukaryotic cell. Somatostatin receptor 3 (SSTR3), one of the GPCRs, is one such important receptor which oversees different cellular processes including cell-to-cell signaling. However, the information available regarding the structural features of SSTR3 responsible for their bioactivity is scarce. In this study, we report a structural understanding of SSTR3-ligand binding that could be helpful in demystifying the structural complexities related to functioning of the receptor. An integrated protocol consisting of different computational structural biology tools including protein structure prediction via comparative modeling, binding site characterization, three-dimensional quantitative structure-activity relationship based on comparative molecular field analysis and comparative molecular similarity indices analysis, density functional theory, and molecular dynamics simulations were performed. Different understandings from the simulation of SSTR3-ligand complexes, mainly the conditions that are favorable for the formation of lowest bioactive state of SSTR3 ligands are reported. In addition to that, we report the important physicochemical descriptors of SSTR3 ligands that could significantly influence their bioactivity. The results of the study could be helpful in developing novel SSTR3 ligands (both agonists and antagonists) with high potency and receptor selectivity.
Keywords: 3D QSAR; DFT; GPCR; molecular dynamics; somatostatin receptor.
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