Discovery of new small molecules inhibitors for EphB4 receptor tyrosine kinase with a fragment-based drug design approach

Erythropoietin-producing hepatocellular carcinoma B4 (EphB4) belongs to the Eph family of receptor tyrosine kinases (RTKs) and plays a significant role in the amplification of many kinds of cancers such as lung cancer, head and neck cancer, and mesothelioma. In this work, we applied a fragment-based drug design strategy to find novel Ephb4 receptor inhibitors as potential therapeutic candidates. A screening of over 269,000 fragments from various libraries has been conducted to determine their affinity for binding EphB4. Using Schrödinger software, 1,000 fragments with the highest docking scores underwent fragment linking to generate 100 new molecules. The EphB4 binding affinity and ADMET characteristics of the top 20 docking score molecules were then examined in more detail. After the best compounds were selected, a molecular dynamics study was conducted to determine the stability of the ligand-receptor complex in the top three molecules. The resultant compound may be investigated further in the context of tyrosine kinase inhibitor drug development.