<br/>C-X-C chemokine receptor 4 (CXCR4) is a G protein coupled receptor (GPCR) that triggers various signaling pathways important for cell migration, cell proliferation and more. In the tumor environment, this leads to an increase in primary tumor tissue growth as well as metastasis to the bone, liver, lung, brain and lymph nodes, making CXCR4 a potential target in drug discovery. Through in-silico high throughput screening our group was able to identify molecules targeting CXCR4. We screened 229,358 compounds from the Natural Products Database, and OMEGA2 was used to generate multiple conformations. Using the x-ray crystal structure of CXCR4 bound with the ligand, we generated the receptor grid. We used FRED docking program to dock the compounds, and ranked the compounds based on binding mode and Chemgauss score. 500 hits were identified and were ranked based on total score, shape score, and lead like properties. From this, we identified four hits (Hit1, Hit2, Hit3, and Hit4). Additionally, Molecular dynamics simulations were carried out on the four hit compounds to comprehend the stability and structural alterations of protein-ligand complexes. For all the selected hits, the RMS deviations of backbone structure were computed and compared. Utilizing the radius of gyration, the compactness of the protein structures was investigated, and it was shown that three hits were sufficient to keep the protein structure compact. Two hits were able to generate effective hydrogen bond interactions, according to an analysis of the average number of hydrogen bonds produced with hit molecules and CXR4. We selected the Hit 1 and Hit 2 as potential CXCR4 inhibitors based on the analysis mentioned above.

Discovery of novel hit molecules targeting cytokine receptor CXCR4 by <i>in-silico</i> high throughput screening approach

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Discovery of novel hit molecules targeting cytokine receptor CXCR4 by in-silico high throughput screening approach