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As such, these two interfacial hydrogen bonds (Table 5), along with the three interfacial salt bridges (Figures 3 and 4) between Arg123, Arg127 and Glu40, led to the establishment of a delicate structural electrostatic balance, while maintaining the structural stabilization of the complex of GLP-R and semaglutide analogues, where such a delicate structural balance in hindsight entails a paradigm shift from the manual design approach in 2011 [27] to an automated systemic approach as described in this manuscript, as it does not appear so straightforwad for a manual design approach to uncover a such a delecate structural balance at a ligand-receptor binding interface [24]

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