Homology modeling of chemokine CCR7, molecular docking, and in vitro studies evidenced plausible immunotherapeutic anticancer natural compounds

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• 作者：Pushpendra Singh ; Ravi Shankar Singh ; Alka Rani ; Felix Bast
• 关键词：Natural compounds ; Cancer ; In silico ; Maestro 9.6 ; In vitro
• 刊名：Medicinal Chemistry Research
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：25
• 期：10
• 页码：2410-2424
• 全文大小：3,625 KB
• 刊物主题：Pharmacology/Toxicology; Biochemistry, general; Cell Biology;
• 出版者：Springer US
• ISSN：1554-8120
• 卷排序：25

文摘

The chemokine receptor 7 is a G-protein coupled, receptors coordinates the migration of cancer cells towards CCL19 and CCL21 constitutively expressed lymphatic organs. Chemokine receptor 7 facilitates cancer progression by generating new lymphatic vessels that serve as conduits for tumor dissemination to lymph nodes. In this context, chemokine receptor 7 inhibitor recently caught an attention for cancer cell growth inhibitor. The 3-D crystalline structure of chemokine receptor 7 not available in protein data bank (PDB), first we predicted the 3-D structure of chemokine receptor 7 and then performed receptor-based molecular docking of chemokine receptor 7 against natural and marine compounds. Semiquantitative polymerase chain reaction (PCR) and quantitative real-time PCR were performed for mRNA expression of chemokine receptor 7 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) used as internal control. The best-docked compounds have been selected for chemokine receptor 7 inhibitors by optimal energy value (Gscore), types of interactions, and conformations. CID6441009, 42607750, 72276, 6711419, 56835050, 65064, 23663412, 72277, 643668, 54679285 compound have a better binding energy −11.35, −10.51, −10.16, −9.98, −9.95, −9.86, −9.83, −9.57, −9.47, and −9.45 respectively against chemokine receptor 7. Protein–ligand interactions profile highlighted that amino acid Glu45, Lys50, Arg54, Lys57, Trp114, Met260, Glu205, Gln227, Gln276, and Asp309 involved in the hydrophobic, hydrogen bonding, and π-π stacking interactions play a central role at the active site. Moreover, treatment with the Epigallocatechin gallate led to down-regulation of mRNA expression of chemokine receptor 7 in HepG2 and PC3 cells. This molecular docking study recapitulates the docking free energy, protein—ligands interactions profile, pharmacokinetic, and the pharmacodynamic parameter of lead molecules, which are extremely helpful to improve the activity of natural and marine compounds against chemokine receptor 7.