<i>In silico</i> designing of drugs for the inhibition of AMF-HER2 complex in trastuzumab resistant breast cancer

Abstract

About 20 to 25% of human metastatic breast cancer over-expresses the human epidermal growth factor receptor 2 (HER2). With the introduction of HER2-targeted therapies, in particular trastuzumab, HER2 status has become more important. The autocrine motility factor (AMF) is a protein factor expressed and secreted by cancer cells. The interaction of AMF with HER2 triggers HER2 phosphorylation, which leads to the development of resistance against trastuzumab. In this work, a theoretical model of AMF was generated using the concepts of homology modeling and loop modeling. The resulting model was validated by Procheck with Ramachandran plot analysis. The ligands generated with the help of Drug bank were docked against AMF using AutoDock Vina in PyRx 0.8. The structure of compound (DB04493) with least binding energy (-15.5 kcal/mol) was varied by using ACD/ChemSketch 8.0 and the docking was done for the resulting 20 new ligands. The study revealed that the compound fructose-6-phosphate (DB04493) has the maximum probability to bind with AMF. The combination of AMF inhibitor with trastuzumab can potentiate the growth inhibitory and anti-invasive actions of trastuzumab in breast cancer cells.