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

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Abstract

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.

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Acknowledgments

We would like to thank Vice Chancellor, Central University of Punjab, Bathinda, Punjab, (India) for supporting this study with infrastructural requirements. We also thank Professor P. Ramarao (Dean, Academic Affairs), Central University of Punjab, Bathinda, Punjab, India, for his suggestions during the course that tremendously helped to improve this article. This study was also supported by a Senior Research Fellowship Grant-in-Aid from Indian Council of Medical Research (ICMR), Government of India awarded to PS and RS Singh.

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Authors and Affiliations

  1. Centre for Biosciences, School of Basic and Applied Sciences, Central University of Punjab, Bathinda, Punjab, 151001, India

    Pushpendra Singh, Alka Rani & Felix Bast

  2. Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226014, India

    Ravi Shankar Singh

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  1. Pushpendra Singh
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  2. Ravi Shankar Singh
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Correspondence to Felix Bast.

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Singh, P., Singh, R.S., Rani, A. et al. Homology modeling of chemokine CCR7, molecular docking, and in vitro studies evidenced plausible immunotherapeutic anticancer natural compounds. Med Chem Res 25, 2410–2424 (2016). https://doi.org/10.1007/s00044-016-1647-2

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