Semaglutide as a Possible Calmodulin Binder: Ligand-Based Computational Analyses and Relevance to Its Associated Reward and Appetitive Behaviour Actions

Abstract

Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has gained considerable attention as a therapeutic agent for type 2 diabetes mellitus and obesity. Despite its clinical success, the precise mechanisms underlying its pharmacological effects remain incompletely understood. In this study, we employed ligand-based drug design strategies to investigate potential off-target interactions of semaglutide. Through a comprehensive in silico screening of semaglutide’s structural properties against a diverse panel of proteins, we have identified calmodulin (CaM) as a putative novel target of semaglutide. Molecular docking simulations revealed a strong interaction between semaglutide and CaM, characterized by favourable binding energies and a stable binding pose. Further molecular dynamics simulations confirmed the stability of the semaglutide–CaM complex, emphasizing the potential for a physiologically relevant interaction. In conclusion, our ligand-based drug design approach has uncovered calmodulin as a potential novel target of semaglutide. This discovery sheds light on the complex pharmacological profile of semaglutide and offers a promising direction for further research into the development of innovative therapeutic strategies for metabolic disorders. The CaM, and especially so the CaMKII, system is central in the experience of both drug- and natural-related reward. It is here hypothesized that, due to semaglutide binding, the reward pathway-based calmodulin system may be activated, and/or differently regulated. This may result in the positive semaglutide action on appetitive behaviour. Further studies are required to confirm these findings.

Exploring the Potential Impact of GLP-1 Receptor Agonists on Substance Use, Compulsive Behavior, and Libido: Insights from Social Media Using a Mixed-Methods Approach

“…Furthermore, both the beneficial effect of GLP-1 RAs on psychopathological aspects (e.g., improved mood) [ 21 , 55 ] and the significant weight loss-related improvement in one’s appearance [ 22 , 56 , 57 , 58 ] could also be hypothesized as being significant factors contributing to reduced drug consumption levels. Previous research has also suggested both direct and indirect effects of GLP-1 RAs on craving, pleasure circuits, and extended networks of substance abuse-related receptor mechanisms [ 6 , 59 ]. Finally, the direct adverse effects of GLP-1 RAs in the context of alcohol abuse are likely to be mainly of gastroenterological relevance [ 60 ], hence acting as anti-addictive/aversive stimuli.…”

“…Interestingly, treatment with semaglutide is also related to reductions in substance use or compulsive behaviors other than eating [ 97 ]. Alterations in dopaminergic pathways in the preclinical model and in human brains both contribute to substance misuse and play a role in compulsive behaviors [ 98 , 99 ], leading to the hypothesis that GLP-1 RAs can act on several factors influencing different maladaptive behaviors, manifesting cross-cutting effects on behavioral and non-behavioral addictions [ 59 ]. The overlap between food and substance cravings at a neural level shows the intricate connection between brain reward pathways.…”