Design, Synthesize CCR1/3/5Antagonists And Study Invasion And Metastasis In Human A549Lung Carcinoma

BackgroundLung cancer is the leading cause of cancer mortality worldwide, accounting for cancerdeaths. Non-small cell lung cancer (NSCLC) accounts for70-80%of the total number oflung cancer. Metastasis and recurrence is the root cause of death in NSCLC patients.Chemokines receptors and their ligands are cytokine superfamily members secreted by thesmall molecule secreted proteins. In recent years, many studies have found that CCL5isrelated to tumor invasion and metastasis.CCL5is a common ligand of CCR1/3/5. It produces the corresponding biologicaleffect binding with CCR1/3/5in vivo. MVC is a CCR5antagonist. It was approved byFDA as anti-HIV-1drug in2007. This study finds that MVC can inhibit invasion andmetastasis in A549cells. A549cells belong to NSCLC with strong ability of invasion andmetastasis, and can express CCR1,3, and5. We guess that CCR1/3/5antagonists havesignificant inhibition of invasion and metastasis of carcinoma cells.ObjectiveExplore the effect of CCR5antagonist MVC in invasion and metastasis of A549cells.Develop3D structures of CCR1and3according to the three-dimensional structure ofCCR5. Design and synthesize CCR1/3/5antagonists using virtual screening and moleculardocking methods. Furthermore, research cellular cytotoxicity, invasion, and metastasis ofCCR1/3/5antagonists in A549cells. This study can provide not only experimentalevidence, but also new ideas to treat NSCLC carcinoma invasion and metastasis.Methods1. Use CCK-8and Transwell methods to research CCR5antagonist MVC inhibitinvasion and metastasis in A549cells.2. Use homology modeling method to develop three-dimensional structure of CCR1and3according to the three-dimensional structure of CCR5.3. Use molecular docking and virtual screening methods to design CCR1/3/5antagonists. 4. Simulate lead compound with CCR1/3/5using molecular dynamics simulationmethod. Calculate binding energy using MM-PBSA method.5. Synthesize three CCR1/3/5antagonists. Identify their structures using H NMR,13CNMR, and IR methods.6. CCK-8and Transwell methods are used to research cellular cytotoxicity, invasion,and metastasis of CCR1/3/5antagonists in A549cells.Results1. MVC could inhibit invasion and metastasis in A549cells.2. We have developed three-dimensional structure of CCR1and3proteins.3. We have designed and synthesized three CCR1/3/5antagonists.4. Molecular dynamics and MM-PBSA results showed that lead compound had astable binding mode with CCR1/3/5.5. CCR1/3/5antagonists didn’t have significant cellular cytotoxicity, but hadsignificant inhibition of carcinoma invasion and metastasis in A549cells.Conclusion1. CADD has extensive and far-reaching applications in carcinoma invasion andmetastasis.2. CCR1/3/5antagonists have no significant cellular cytotoxicity.3. CCR1/3/5antagonists have significantly inhibition of carcinoma invasion andmetastasis in A549cells.