In silico screening combined with bioactivity evaluation to identify AMI-1 as a novel anticancer compound by...

Recently, some studies have proven that AXL plays a crucial role in the drug resistance of tumors. At present, no AXL inhibitors on the market and it is essential to discover novel compounds targeting AXL to overcome resistance. In this work, based on the anchor structure, 21,313 compounds were obtained by substructure search from more than 400,000 compounds. Then, the Qvina and Ledock were selected for virtual screening to obtain 17 compounds. Next, four compounds (ARRY614, AMI-1, NG25, and Butein) were selected for bioactivity evaluation after hydrogen bond and cluster analysis. Further activity evaluation suggested that the compound AMI-1 is a novel AXL inhibitor with an IC₅₀ value of 1.13 uM. In addition, molecular dynamics simulation demonstrated that compound AMI-1 contained lower binding energy and more key residues than the other three compounds, showing the best inhibitory activity against AXL. Finally, further MM/PBSA prediction showed that AMI-1 is more sensitive to mutant protein 3IKA than wildtype protein 1M17, which means that the AMI-1 may be helpful to overcome the resistance of EGFR^T790M mutations. In conclusion, this work successfully discovered a novel compound with moderate inhibitory activity against AXL by a drug discovery workflow, which also could be applied to discover active compounds for other targets quickly.Communicated by Ramaswamy H. Sarma.