Streamlined Protein‐Protein Interface Loop Mimicry

Abstract

AbstractCyclic peptides comprising endocyclic organic fragments, “cyclo‐organopeptides”, can be probes for perturbing protein‐protein interactions (PPIs). Finding loop mimics is difficult because of high conformational variability amongst targets. Backbone Matching (BM), introduced here, helps solve this problem in the illustrative cases by facilitating efficient evaluation of virtual cyclo‐organopeptide core‐structure libraries. Thus, 86 rigid organic fragments were selected to build a library of 602 cyclo‐organopeptides comprising Ala and organic parts: “cyclo‐{‐(Ala)n‐organo‐}”. The central hypothesis is “hit” library members have accessible low energy conformers corresponding to backbone structures of target protein loops, while library members which cannot attain this conformation are probably unworthy of further evaluation. BM thereby prioritizes candidate loop mimics, so that less than 10 cyclo‐organopeptides are needed to be prepared to find leads for two illustrative PPIs: iNOS ⋅ SPSB2, and uPA ⋅ uPAR.