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Structural Evaluation and Binding Mode Analysis of CCL19 and CCR7 Proteins—Identification of Novel Leads for Rheumatic and Autoimmune Diseases: An Insilico study

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Abstract

The Human Chemokine (C–C motif) ligand 19 (CCL19) protein plays a major role in rheumatic and autoimmune diseases. The 3D models of the CCL19 and its receptor CCR7 are generated using homology modeling and are validated using standard computational protocols. Disulfide bridges identified in 3D model of CCL19 protein give extra stability to the overall protein structure. The active site region of protein CCL19, containing N-terminal amino acid residues (Gly22 to Leu31), is predicted using in silico techniques. Protein–protein docking studies are carried out between the CCL19 and CCR7 proteins to analyse the active site binding interactions of CCL19. The binding domain of CCL19 is subjected to structure-based virtual screening of small molecule databases, and identified several bioisosteric ligand molecules having pyrrolidone and piperidone pharmacophores. The prioritized ligands with acceptable ADME properties are reported as new leads for the design of potential CCL19 antagonists for rheumatic and autoimmune disease therapies.

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Acknowledgements

The authors SV, RD, BK, NN, RV, VR, and RKD are thankful to The Principal and The Head, Department of Chemistry, University College of Science, Osmania University, Hyderabad for providing facilities to carry out this work. SV and RKD are grateful to University Grants Commission-New Delhi for Junior Research Fellowship (JRF) under Basic Scientific Research (BSR), Research Fellowship in Sciences for Meritorious Students Scheme (RFSMS) (File no. 1043/A/2/Chem/BSR/2013–2014), and VR is greatly thankful to Council of Scientific and Industrial Research-India (File No. 09/132(0821)/2012-EMR-I) for financial support.

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  1. Department of Chemistry, University College of Science, Osmania University, Tarnaka, Hyderabad, Telangana State, 500007, India

    Santhi Prada Vellanki, Ramasree Dulapalli, Bhargavi Kondagari, Rajender Vadija, Vishwanath Ramatenki, Rama Krishna Dumpati & Uma Vuruputuri

  2. Department of Chemistry, Post Graduate College of Science, Saifabad, Osmania University, Hyderabad, Telangana State, 500004, India

    Navaneetha Nambigari

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  1. Santhi Prada Vellanki
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The authors of the manuscript entitled “Structural Evaluation and Binding Mode Analysis of CCL19 and CCR7 proteins—Identification of Novel Leads for Rheumatic and Autoimmune Diseases: An Insilico Study” have no conflict of interest.

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12539_2017_212_MOESM1_ESM.tif

ProSA energy plots of CCL19 and CCR7 proteins. The ProSA energy profile graphs (Fig 1a and b) show that most of the amino acids in the CCL19 and CCR7 proteins fall in negative ProSA energy regions (TIF 20958 KB)

12539_2017_212_MOESM2_ESM.tif

Transmembrane domain prediction for CCR7 protein using SPLIT4.0 and NCBI servers. Secondary structure prediction for CCR7 protein obtained using the method of preference functions for proteins in the SPLIT 4.0 Server (Fig 2a). Red line, represents the transmembrane helix preference (THM index); blue line, beta preference (BET index); grey line, modified hydrophobic moment index (INDA index); violet boxes (below abscissa), predicted transmembrane helix position (DIG index). Seven transmembrane domains of CCR7 protein, predicted by BLAST Server, are represented as grey bar (Fig 2b) (TIF 9662 KB)

12539_2017_212_MOESM3_ESM.tif

Interactions between the CCL19 protein and the docked ligand with the top prioritized glide score. Docked molecules obtained after virtual screening studies. Consistent binding interactions are observed at Asp 28 and Leu 31 residues which are found in DCCL motif of the CCL19 protein (TIF 18334 KB)

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Vellanki, S.P., Dulapalli, R., Kondagari, B. et al. Structural Evaluation and Binding Mode Analysis of CCL19 and CCR7 Proteins—Identification of Novel Leads for Rheumatic and Autoimmune Diseases: An Insilico study. Interdiscip Sci Comput Life Sci 10, 346–366 (2018). https://doi.org/10.1007/s12539-017-0212-0

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