Molecular simulations of SSTR2 dynamics and interaction with ligands

Area of Science:

• Pharmacology
• Biochemistry
• Computational Biology

Background:

• Somatostatin is a peptide hormone regulating growth and metabolism via G-protein coupled somatostatin receptors.
• Somatostatin receptor subtype 2 (SSTR2) is crucial for neuroendocrine tumor therapy, with analogues in clinical use.
• Understanding SSTR2 dynamics is key to designing effective therapeutic agents.

Purpose of the Study:

• To conduct a systematic computational study on SSTR2 dynamics in active agonist-bound, inactive antagonist-bound, and apo inactive states.
• To rationalize the binding mechanisms of different ligands to SSTR2 using molecular dynamics simulations.
• To identify key interactions that differentiate agonist and antagonist binding for improved drug design.

Main Methods:

• Utilized extensive, recently available SSTR2 experimental structures.
• Performed multi-copy molecular dynamics simulations lasting microseconds.
• Employed interaction fingerprint analyses and free energy calculations.

Main Results:

• The apo SSTR2 form exhibits greater flexibility than ligand-bound (holo) forms.
• Extracellular loop 2 closure was observed with the agonist octreotide but not the antagonist CYN154806.
• Agonists and antagonists share interactions in the binding pocket's core but differ in interactions at the pocket's periphery and extracellular loops.

Conclusions:

• Distinct interaction patterns at the SSTR2 binding site periphery differentiate agonists from antagonists.
• These findings provide insights into SSTR2 conformational dynamics and ligand interactions.
• The study supports the rational design of novel somatostatin-based compounds for neuroendocrine tumor theranostics.