FRAGMENT-BASED DRUG DESIGN TO INHIBIT DNA METHYLTRANSFERASE 1 (DNMT1) FOR BREAST CANCER THERAPY
Keywords:Breast cancer, DNA methyltransferase, natural products, fragment-based drug design, molecular docking simulation
Breast cancer is the most substantial cancer among women in the world. The uncontrollably high DNA Methyltransferase-1 (DNMT1) activity which leads to abnormal gene expression is one of the primary cause of breast cancer. Therefore, DNMT1, as an essential enzyme in epigenetic regulation, is considered as a potential therapeutic target for breast cancer treatment. In this research, the inhibitors of DNMT1 were designed through fragment-based drug design. About 168,646 natural products from PubChem database were used as fragment candidates. Initial screening based on toxicity and Lipinski’s Rule of Three was performed to obtain 2,601 favorable fragments. Pharmacophore-based rigid and flexible molecular docking simulation was employed with DNMT1 as the target protein. The selected fragments from docking simulation underwent fragment linking modification and second toxicity screening, generating 23 ligands. Subsequently, the newly designed ligands were subjected to pharmacophore-based flexible molecular docking simulation. Two ligands, HAMI 9 and HAMI 14, with Gibbs free binding energy of -11.6095 and -11.5904 kcal/mol, respectively, are considered as a promising inhibitor of DNMT1. The pharmacological properties of the ligands were analyzed using DataWarrior v04.07.02, Toxtree v2.6.13, SwissADME, admetSAR, and Molinspiration. The ligands show not only superior affinity and molecular interaction to DNMT1 but also have advantageous pharmacological properties compared to the standards. Additional in silico as well as in vivo experiments are needed to further assess the potency of HAMI 9 and HAMI 14 as drug candidates against breast cancer.