Exploring antiproliferative potential, in silico docking, and molecular dynamics of pyrimidine-morpholine hybrid molecules

Cancer remains a leading cause of death worldwide, highlighting the urgent need for novel therapeutic agents. Pyrimidine-morpholine hybrid compounds have been synthesized as potential multitarget anticancer agents for investigation against lung (A549) and liver (HepG2) cancer cell lines. The antiproliferative effects of the synthesized compounds were evaluated using the MTT assay. Molecular docking studies were conducted to assess the binding affinity of these compounds to the epidermal growth factor receptor (EGFR). Density functional theory (DFT) calculations were performed to analyze electronic properties, and molecular dynamics (MD) simulations over 100 ns were used to investigate the stability of the compound-EGFR complex. MM-GBSA analysis was applied to identify key intermolecular forces contributing to binding. Compounds containing electron-withdrawing groups, such as compound 2c with a 4-cyano substituent, demonstrated the highest antiproliferative activity with IC 50 values of 17.2 ±1.01 μM for A549 cells and 12.1 ± 1.01 μM for HepG2 cells, surpassing reference drugs like cisplatin and 5-fluorouracil in some cases. Docking results showed strong binding interactions through hydrogen bonding, π-π stacking, and hydrophobic forces, with compound 2c exhibiting the lowest binding energy (−8.1 kcal/mol). DFT calculations supported these findings, indicating enhanced reactivity due to electron-withdrawing groups. MD simulations confirmed the stability of the 2c-EGFR complex, while MM-GBSA analysis identified van der Waals interactions as major contributors to binding affinity. Pyrimidine-morpholine hybrids exhibit promising antiproliferative activity combined with favorable electronic and structural characteristics, positioning them as potential multitarget anticancer agents. Further in vivo studies are necessary to validate and advance their therapeutic applicability.