In silico Study on the Binding Interactions of SSTA and ¹⁸F-SSTA Towards Somatostatin Receptor Subtype 2

Background: Somatostatin analogs (SSTAs) are versatile drugs that target a group of proteins known as somatostatin receptors. SSTAs are used for the treatment and PET-molecular imaging of Neuro Endocrine Tumors (NET), for they are labeled with the radionuclide ¹⁸F, a positron emitter radionuclide. Objective: The aim of this work was to theoretically study the binding interactions of SSTA labeled with ¹⁸F (half-life of 109.7 min) and somatostatin receptor subtype 2. As the labeling of SSTA with ¹⁸F required the use of a prosthetic group, a hydrophilicity enhancer, and a linker, the influence of these traits on the interactions of ¹⁸F-SSTA with the SSTR-2 binding site was studied. Methods: The binding modes of ¹⁸F-labeled analogues with SSTR-2 were studied by using protein homology modelling, non-equilibrium molecular dynamics, and molecular docking calculations, by means of three docking software: MVD, MOE, and VINA. Results: The results showed the main role of Asp122, Asn276, Phe272 and Phe294 from the SSTR-2 binding site, which form interactions with residues Lys, Trp, Tyr, and Thr from ¹⁸F-labeled somatostatin analogues. Conclusion: The interaction between Lys (from 18F-SSTA) and Asp122 (from SSTR-2) was identified as the most energetic and considered the one that drives the binding between ¹⁸F-SSTA and SSTR-2 (the anchor interaction). Despite the presence of prosthetic groups, linkers, and hydrophilicity enhancers, all the studied ¹⁸F-SSTA formed the anchor interaction. The trend in the results agreed with the experimental reports, identifying the main role of Asp122 in the binding of somatostatin-14 to SSTR-2.