Screening Peptide Motif Mimics for Drug Discovery

The structures of the NITVK and VQDLL motifs of SspB were taken directly from the Streptococcus gordonii SspB C-terminal domain crystal structure (Protein Data Bank entry 2WZA) (31 (link)). The structure was processed using the Protein Preparation Wizard in Maestro (Schrödinger release 2018-1; Schrödinger, LLC, New York, NY). The similarity searches for the NITVK and VQDLL motifs were performed with Surflex-sim version 2.601 (32 (link)) using two approaches. The first approach was to use all atoms of the peptide structures for the NITVK and VQDLL motifs as the hypothetical ligand. The second approach was to use the side chains of residues for the NITVK motif and the side chains of residues VLL for the VQDLL motif. The screened libraries were created from the ZINC (28 (link)) drug-like library (ZINC 2014 version) containing 24,877,119 compounds and the ZINC 15 (29 (link)) drug-like library (ZINC 2016 version) containing 17,244,856 compounds. The results were ranked, and the top 500 compounds of each screen were retained. The selection of compounds was based on compound score; diversity, by eliminating compounds that were structurally similar to a higher scoring compounds; and finally, compounds that were commercially readily available for purchase. Seventeen compounds and 16 compounds were purchased (MolPort SIA, Riga, Latvia) for the NITVK and VQDLL motifs, respectively.