ORIGINAL ARTICLE Identification of Novel Peptides Targeting DNA Methyltransferase 1 (DNMT-1) for Breast Cancer Treatment Mutiara Saragih 1 & Filia Stephanie 1 & Ahmad H. Alkaff 1 & Usman S. F. Tambunan 1 Received: 11 March 2020 /Accepted: 14 August 2020 # Sociedade Brasileira de Farmacognosia 2020 Abstract Epigenetic alteration shows an essential role in the process of breast cancer cell proliferation and propagation. DNA methyl- transferase (DNMT) is responsible for DNA methylation, resulted in the epigenetic silencing of multiple genes. Hence, inhibiting DNMT-1 is a promising way to block uncontrolled DNA methylation. This study aimed to retrieve a potential peptide compound as DNMT-1 inhibitor due to its desirable properties as drug candidate through virtual screening and molecular docking simula- tion. A total of 51,957 peptide ligands from PubChem database underwent computational pharmacological screening to eliminate compounds with undesired characteristics. Molecular docking simulation was done with generated pharmacophore features, and the potential ligands with good ΔG binding, RMSD value, and molecular interaction were cyclized to increase the bioavailability of the peptides. Cyclic peptide ligands were tested for its interaction with DNMT-1 protein and ADME-Tox properties. From these steps, three cyclic peptide ligands showed desirable characteristics as a new drug candidate for the DNMT1 inhibitor. Keywords Breast cancer . Epigenetic . DNA methyltransferase . Cyclization . Pharmacophore . ADME-Tox Introduction Cancer can be described as a disease in which a group of abnormal cells grows uncontrollably by disregarding the nor- mal rules of cell division. Cancer is the second leading cause of mortality worldwide (Hassanpour and Dehghani 2017). Based on the World Health Organization, there was about 9.6 million deaths caused by cancer in 2018. Approximately 1.5 million women worldwide are diagnosed with breast can- cer each year, resulted in 1.3 million mortality (Pasculli et al. 2018). Most of cancer cases are identified to be driven by the accumulation of genetic abnormalities involving mutations in oncogenes or tumor suppressor genes. The genetic muta- tions, either inherited or sporadic, may result in the activation of oncogenes and the inactivation of tumor suppressor genes (Connolly and Stearns 2012). The genome consists informa- tion in two forms, genetic and epigenetic. The genetic infor- mation serves as the blueprint for all the protein necessary to create a living organism, while the epigenetic information consists of the instruction on how, where, and when the ge- netic information should be used (Robertson 2001). Epigenetics has been found as an essential role of the phe- notype as it organizes when and which genes should be expressed without altering DNA sequence. Epigenetic modi- fication may cause the activation of oncogenes and the silenc- ing of tumor suppressor genes. There are three major epige- netic modifications occurred in breast cancer proliferation, such as DNA methylation, post-translational modifications of histones, and miRNA dysregulation. DNA methylation is one of the most researched topics on epigenetic modification in humans (Basse and Arock 2015). DNA methylation plays an essential role in epigenetic regu- lation of gene expression in mammalian cells. DNA methylation is an epigenetic change mediated by DNMT that resulted in the addition of a methyl group at the carbon-5 (C5) position of the pyrimidinic ring. There are three types of DNMT enzymes in the human. It consists of two de novo methyltransferase (DNMT3A and DNMT3B) and the maintenance methyltransferase (DNMT1). The DNMT1 is specifically responsible for Electronic supplementary material The online version of this article (https://doi.org/10.1007/s43450-020-00086-6) contains supplementary material, which is available to authorized users. * Usman S. F. Tambunan usman@ui.ac.id 1 Bioinformatics Research Group, Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Indonesia, Depok, West Java 16424, Indonesia https://doi.org/10.1007/s43450-020-00086-6 / Published online: 9 September 2020 Revista Brasileira de Farmacognosia (2020) 30:641–651