Reveal the interaction mechanism of five old drugs targeting VEGFR2 through computational simulations

Abstract VEGFR2, vascular endothelial growth factor receptor 2, plays an important role in anti-angiogenesis and is an effective target for inhibiting tumor cell proliferation and metastasis. Many small molecule inhibitors have so far exhibited fine therapeutic effects but do not rule out some adverse reactions. From the perspective of the new use of old drugs, we use a combination of two different docking methods, molecular dynamics simulations and quantum-chemical calculations to acquire potential anti-angiogenesis inhibitors from the library of FDA-approved drugs. We attain five FDA-approved old drugs from Drugbank as potential inhibitors against VEGFR2. Therein, the anti-tumor effects of three compounds, including vilazodone (psychiatric drug), pranlukast and zafirlukast (asthma drugs), have been reported by previous experiments but no anti-tumor data is available for the other two compounds, including antrafenine (analgesic and anti-inflammatory drug) and iloperidone (psychiatric drug). These five compounds exhibit more stable interaction than sorafenib as a market-oriented drug targeting VEGFR2. In parallel, there is a most stable interaction for zafirlukast while a weakest interaction for iloperidone with VEGFR2. We show that these five compounds bind with the hydrophobic cavity of VEGFR2, then forming hydrogen bond interactions with three key residues, Glu-885, Cys-919 and Asp-1046. Lys-868 and Phe-1047 play an important role in stabilizing the interaction conformation. The binding poses of pranlukast and vilazodone are similar to that of sorafenib, whereas antrafenine and zafirlukast act differently from sorafenib, focusing on the direction difference of the respective ring structure. This work may help to develop new and effective anti-angiogenic inhibitors.