Occurrence of the d-proline chemotype in enzyme inhibitors

Natural and nonnatural amino acids represent important building blocks for the development of peptidomimetic scaffolds, especially for targeting proteolytic enzymes and for addressing protein–protein interactions. Among all the different amino acids derivatives, proline is particularly relevant in chemical biology and medicinal chemistry due to its secondary structure’s inducing and stabilizing properties. Also, the pyrrolidine ring is a conformationally constrained template that can direct appendages into specific clefts of the enzyme binding site. Thus, many papers have appeared in the literature focusing on the use of proline and its derivatives as scaffolds for medicinal chemistry applications. In this review paper, an insight into the different biological outcomes of d-proline and l-proline in enzyme inhibitors is presented, especially when associated with matrix metalloprotease and metallo-β-lactamase enzymes.