Role of Side‐Chain Bioisosteres in Determining the Binding Affinity of Click Chemistry Derived RGD Peptidomimetics to αvβ3 Integrin

Triazole-containing Arg-Gly-Asp (RGD) peptidomimetics capable of interacting with αvβ3 integrin were developed through click chemistry. The role of the diverse range of guanidine bioisosteres for the arginine mimetic moiety was evaluated in vitro together with different appendages on the aspartic acid side of the peptidomimetic. The corresponding azides and alkynes were constructed through the application of simple modular reactions. Integrin binding assays allowed the best guanidine bioisostere for binding activity to be selected; the aromatic ring at the azide fragment bearing the aspartic acid moiety proved to be unnecessary. Molecular modelling calculations of a hit compound showed that the triazole and 2-aminopyridine rings were involved in important π-stacking interactions with Tyr178.