The cyclic peptide hormone somatostatin regulates physiological processes involved in growth and metabolism, through its binding to G-protein coupled somatostatin receptors. The isoform 2 (SSTR2) is of particular relevance for the therapy of neuroendocrine tumours for which different analogues to somatostatin are currently in clinical use. We present an extensive and systematic computational study on the dynamics of SSTR2 in three different states: active agonist-bound, inactive antagonist-bound and apo inactive. We exploited the recent burst of SSTR2 experimental structures to perform μs-long multi-copy molecular dynamics simulations to sample conformational changes of the receptor and rationalize its binding to different ligands (the agonists somatostatin and octreotide, and the antagonist CYN154806). Our findings suggest that the apo form is more flexible compared to the holo ones, and confirm that the extracellular loop 2 closes upon the agonist octreotide but not upon the antagonist CYN154806. Based on interaction fingerprint analyses and free energy calculations, we found that all peptides similarly interact with residues buried into the binding pocket. Conversely, specific patterns of interactions are found with residues located in the external portion of the pocket, at the basis of the extracellular loops, particularly distinguishing the agonists from the antagonist. This study will help in the design of new somatostatin-based compounds for theranostics of neuroendocrine tumours.
Introduction: Several studies have supported the evidence that attachment styles are a central factor in adolescent gambling problems. On this theoretical basis, the aim of the present study is to analyze a hypothesized mediation model exploring both the direct and indirect effects of insecure attachment on gambling disorder by investigating the role of the developmental perspective, theory of mind (friend) and adaptive response in that relationship. Method: The sample consists of 178 adolescents who underwent the Measures: South Oaks Gambling Screen—Revised for Adolescents and Friends and Family Interview. Result: The mediation analysis was conducted following Hayes’ (2018) procedure, using Model 6. The results showed a significant association between insecure attachment and gambling disorder (β = 0.669; p < 0.001). The findings also highlighted a significant chained mediation model in which insecure attachment negatively influenced the developmental perspective (β = −0.742; p < 0.001), which affected the theory of mind toward one’s own best friend (β = 0.352; p < 0.001). Conclusions: The results highlighted a significant role of insecure attachment in predicting the symptomatic expression of gambling among adolescents, specifically impacting the development perspective, theory of mind toward one’s best friend and adaptive response to stress, which were linked to each other by a sequential influence. Therefore, our results showed that a poor developmental self-vision predicted a dysfunctional theory of mind toward the best friend. This could hinder the formation of positive peer relationships, which are crucial for the development of one’s identity.
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