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.
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.
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