However, the number of potent and selective inhibitors remains small and the community still does not have adequate tools to target all methyltransferases that are implicated in human disease. For this reason EZH2 remains an important target for inhibitor design. The pharmacological properties of peptidic inhibitors make their use in the development of cancer therapeutics difficult. However, the specificity with which they can act with their binding partner make them desirable for the development of chemical probes for the interrogation of methyltransferase and chromatin biology. Peptide inhibitors are generally more specific than small molecule inhibitors as they often more closely resemble the natural binders of many target proteins. The aim of this work was to find specific peptidic inhibitors of EZH2 using a computational de novo peptide buy Sirtuin modulator 1 design framework. This framework consists of three stages. The first stage is an optimization-based sequence selection stage that aims for Fruquintinib stability of the designed sequence in the given peptide template structure through the minimization of a potential energy. The second stage determines the fold specificity of the peptide for the template structure in comparison to the native structure. The third stage determines the approximate binding affinity of the design peptides for EZH2 in order to assess their preference for the bound versus unbound state. Through these three stages of increasing computational complexity, one aims to produce peptides that are specific for the target EZH2 structure. In addition to the application of the designed peptides as chemical probes for the interrogation of chromatin biology, experimentally validated peptides are of significant importance to the further development of the peptide design framework. Retrospective analysis of the structural template and biological constraints used as input into the sequence selection stage can demonstrate what types of constraints are useful for future methyltransferase design, as well as peptidic inhibitor design as a whole. The computational, three-stage de novo peptide design method used in this study was focused on the development of novel peptidic inhibitors of enhancer of zeste homolog 2. The first stage of the method is a seq
