Docking and molecular dynamics predicted B-DNA and dihydropyrimidinone selenoesters interactions elucidating antiproliferative effects on breast adenocarcinoma cells

Dihydropyrimidinones have demonstrated different biological activities including anticancer properties. Cytotoxic potential and antiproliferative potential of new dihydropyrimidinone-derived selenoesters (Se-DHPM) compounds were assessed <i>in vitro</i> against the breast adenocarcinoma cells (MCF-7). Among the eight Se-DHPM compounds tested just 49A and 49F were the most cytotoxic for MCF-7 and the most selective for the non-tumor strain (McCoy) and reduced cell viability in a time- and concentration-dependent manner. Compounds 49A and 49F increased the rate of cell death due to apoptosis and necrosis comparatively to the control, however only the 49F showed antiproliferative potential, reducing the number of colonies formed. In the molecular assay 49A interacts with CT-DNA and caused hyperchromism while 49F caused a hypochromic effect. The intercalation test revealed that the two compounds caused destabilization in the CT-DNA molecule. This effect was evidenced by the loss of fluorescence when the compounds competed and caused the displacement of propidium iodide. Simulations (docking and molecular dynamics) using B-DNA brought a greater understanding of ligand–B-DNA interactions. Furthermore, they predicted that the compounds act as minor groove ligands that are stabilized through hydrogen bonds and hydrophobic interactions. However, the form of interaction foreseen for 49A was more energetically favorable and had more stable hydrogen bonds during the simulation time. Despite some violations foreseen in the ADMET for 49F, the set of other results point to this Se-DHPM as a promising <i>leader</i> compound with anti-tumor potential for breast cancer. Communicated by Ramaswamy H. Sarma