Computer-aided design of peptidomimetic molecules targeting cadherin-mediated protein-protein interactions

Cadherins are cell-cell adhesion proteins which are overexpressed in several solid tumors. They contain an extracellular region consisting of five immunoglobulin-like domains (EC1–EC5) that extend from the cell surface. In 1995, structural data of the N-cadherin suggested an homodimeric interface involving the peptide chains HAVDI and INPI contained in the middle EC1 sequence. Based on these studies, mimics of His-Ala-Val sequence have been patented. More recently, the crystal structures of the complete (EC1-EC5) ectodomains of N- and E-cadherins have been solved highlighting that cadherins dimerize through a ‘strand-swap’ trans-adhesive interface involving the N-terminal EC1 domains. In this framework, a thorough study of the adhesion dimer structures was attempted with the aim of characterizing cadherin binding interfaces and developing computational tools for the design of small peptidomimetics that target the homophilic interactions of the extracellular cadherin domains. Possible approaches included mapping the hotspot interactions into pharmacophores for database screening and mapping the epitope of one of the proteins onto a small peptidomimetic. The communication will discuss the first results obtained in the computer-aided design, focusing on the most promising peptidomimetics found by virtual screening of database and rational design of small libraries of tetrapeptide mimics (Figure 1). The synthesis of few candidates has already been completed and their biological evaluation started.