@ARTICLE{10.3389/fchem.2020.573259, AUTHOR={Santini, Brianda L. and Zacharias, Martin}, TITLE={Rapid in silico Design of Potential Cyclic Peptide Binders Targeting Protein-Protein Interfaces}, JOURNAL={Frontiers in Chemistry}, VOLUME={8}, YEAR={2020}, URL={https://www.frontiersin.org/articles/10.3389/fchem.2020.573259}, DOI={10.3389/fchem.2020.573259}, ISSN={2296-2646}, ABSTRACT={Rational design of specific inhibitors of protein-protein interactions is desirable for drug design to control cellular signal transduction but also for studying protein-protein interaction networks. We have developed a rapid computational approach to rationally design cyclic peptides that potentially bind at desired regions of the interface of protein-protein complexes. The methodology is based on comparing the protein backbone structure of short peptide segments (epitopes) at the protein-protein interface with a collection of cyclic peptide backbone structures. A cyclic peptide that matches the backbone structure of the segment is used as a template for a binder by adapting the amino acid side chains to the side chains found in the target complex. For a small library of cyclic peptides with known high resolution structures we found for the majority (~82%) of 154 protein-protein complexes at least one very well fitting match for a cyclic peptide template to a protein-protein interface segment. The majority of the constructed protein-cyclic peptide complexes was very stable during Molecular Dynamics simulations and showed an interaction energy score that was typically more favorable compared to interaction scores of typical peptide-protein complexes. Our cPEPmatch approach could be a promising approach for rapid suggestion of cyclic peptide binders that could be tested experimentally and further improved by chemical modification.} }