Discovery of novel DNMT-1 inhibitor by fragment-based drug design as a potential breast cancer treatment

Abstract

Breast cancer is the most common and lethal type of cancer among women in the world. Epimutation is the leading cause of the tumorigenesis of breast cancer. DNA methyltransferase 1 (DNMT1) is the key enzyme involved in the regulation of DNA methylation pattern. In this research, the fragment-based drug design approach on natural products was performed to discover a novel inhibitor of the DNMT1 as a therapeutic strategy against breast cancer. About 2,601 fragments out of 168,646 compounds were obtained from the Lipinski's Rule of Three and toxicity screening. The fragments were docked into the S-Adenosyl-L-methionine (SAM) binding site of DNMT1. The potential fragments were merged with S-Adenosyl-L-homocysteine (SAH), generating nine ligands. The ligands underwent flexible docking simulation and ADME-Tox prediction by using AdmetSAR, Toxtree, SwissADME software. Three ligands show favorable characteristics as a new drug candidate for the DNMT1 inhibitor according to the interaction of the amino acid residues, RMSD, and δGbinding. MAHI1 being the best ligands in term of δGbinding -12.6300 kcal/mol, molecular interaction, and pharmacological properties.