Interaction of Radiopharmaceuticals with Somatostatin Receptor 2 Revealed by Molecular Dynamics Simulations

The development of drugs targeting somatostatin receptor2 (SSTR2),generally overexpressed in neuroendocrine tumors, is focus of intenseresearch. A few molecules in conjugation with radionuclides are inclinical use for both diagnostic and therapeutic purposes. These radiopharmaceuticalsare composed of a somatostatin analogue biovector conjugated to achelator moiety bearing the radionuclide. To date, despite valuableefforts, a detailed molecular-level description of the interactionof radiopharmaceuticals in complex with SSTR2 has not yet been accomplished.Therefore, in this work, we carefully analyzed the key dynamical featuresand detailed molecular interactions of SSTR2 in complex with six radiopharmaceuticalcompounds selected among the few already in use (Cu-64/Ga-68-DOTATATE, Ga-68-DOTATOC, Cu-64-SARTATE)and some in clinical development (Ga-68-DOTANOC, Cu-64-TETATATE). Through molecular dynamics simulations and exploitingrecently available structures of SSTR2, we explored the influenceof the different portions of the compounds (peptide, radionuclide,and chelator) in the interaction with the receptor. We identifiedthe most stable binding modes and found distinct interaction patternscharacterizing the six compounds. We thus unveiled detailed molecularinteractions crucial for the recognition of this class of radiopharmaceuticals.The microscopically well-founded analysis presented in this studyprovides guidelines for the design of new potent ligands targetingSSTR2.