A virtual library of small molecules mimicking dipeptides

Virtual combinatorial libraries are prevalent in drug discovery due to improvements in the prediction of synthetic reactions that can be performed. This has gone hand in hand with the development of virtual screening capabilities to effectively screen the large chemical spaces spanned by exhaustive enumeration of reaction products. In this study, we generated a small‐molecule dipeptide mimic library to target proteins binding small peptides. The library was created based on the general idea of peptide synthesis, that is, amino acid mimics were reacted in silico to form the dipeptide mimics, yielding 2,036,819 unique compounds. After docking calculations, two compounds from the library were synthesized and tested against WD repeat‐containing protein 5 (WDR5) and histamine receptors H1–H4 to evaluate whether these molecules are viable in assays. The compounds showed the highest potency at the histamine H3 receptor, with Ki values in the two‐digit micromolar range. A library of small molecules was created to mimic the action of dipeptides. This was done by performing in silico reactions of amino acid mimics (building blocks) with known robust reactions. The library was validated by synthesizing two compounds and testing them in vitro against different proteins.