A Novel Pyridopyrimidine Derivative as a Potential Breast Cancer Agent: DFT, Docking, MD Simulation, and Cytotoxic Studies

ABSTRACT Breast cancer is a pervasive and deadly disease, affecting women worldwide. Chemotherapy for breast cancer primarily targets receptors, such as ERα, PR, CDK2, and EGFR, whose overexpression contributes to the initiation and progression of cancer. In this study, a tetrahydropyrido[4,3‐ d ]pyrimidine derivative 4‐(4‐methylpiperazin‐1‐yl)‐5,6,7,8‐tetrahydropyrido[4,3‐ d ]pyrimidine was used as an inhibitor of these receptors. It employs density functional theory calculations and experimental investigations of the compound. Molecular docking studies were conducted to evaluate the potential of the compound as an inhibitor of CDK2 (2J9M), PR (4OAR), EGFR (1M17 & 2J6M), ERα (3ERT), and resulting binding affinities were −7.2, −6.9, −6.6, −6.2, and −6.9 kcal/mol, respectively. Molecular dynamics simulations performed on docked complex with highest binding affinity further confirm its dynamic stability inside the binding cavity. The cytotoxic performance against the MCF‐7 and MDA‐MB‐231 breast cancer cell lines was examined using MTT assay, and obtained IC 50 values were 62.5 and 500 µg/mL, respectively. Dual AO/PI staining was used to evaluate the ability of the compound to induce apoptosis in MCF‐7 cells. Furthermore, the compound met various pharmacokinetic criteria, suggesting its drug‐like properties. Considering the effectiveness of pyrimidine–piperazine derivatives in cancer treatment, this compound holds promise as a lead compound for novel breast cancer therapies.