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. 2017 Apr 21;7(1):1029.
doi: 10.1038/s41598-017-01254-w.

In-Silico Drug discovery approach targeting receptor tyrosine kinase-like orphan receptor 1 for cancer treatment

Onkar Nath  1 , Archana Singh  2 , Indrakant K Singh  3   4
Affiliations

In-Silico Drug discovery approach targeting receptor tyrosine kinase-like orphan receptor 1 for cancer treatment

Onkar Nath et al. Sci Rep. .

Abstract

Receptor tyrosine kinases (RTK) are important cell signaling molecules that influence many cellular processes. Receptor tyrosine kinase such as orphan receptor 1 (Ror1), a surface antigen, is a member of the RTK family of Ror, which plays a crucial role in cancers that have high-grade histology. As Ror1 has been implicated to be a potential target for cancer therapy, we selected this protein for further investigation. The secondary and tertiary structure of this protein was determined, which revealed that this protein contained three β-sheets, seven α-helices, and coils. The prediction of the active site revealed its cage-like function that opens for ligand entry and then closes for interacting with the ligands. Optimized ligands from the database were virtually screened to obtain the most efficient and potent ones. The screened ligands were evaluated for their therapeutic usefulness. Furthermore, the ligands that passed the test were docked to the target protein resulting in a few ligands with high score, which were analyzed further. The highest scoring ligand, Beta-1, 2,3,4,6-Penta-O-Galloyl-D-Glucopyranose was reported to be a naturally occurring tannin. This in silico approach indicates the potential of this molecule for advancing a further step in cancer treatment.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Secondary structure analysis of the Ror1 protein.
Figure 2
Figure 2
Template search using BLASTp tool.
Figure 3
Figure 3
(a) Z-score and number of amino acids indicating accuracy and completeness of predicted structure (b) Z-Score plot of model predicted by I-Tasser with structures available in database (c), Energy plot for amino acid residues for the 3D-structure of I-Tasser.
Figure 4
Figure 4
3D-Structure of Ror1 protein and its actives sites.
Figure 5
Figure 5
Domain Analysis by CD Search indicating similarity to tyrosine kinase domain.
Figure 6
Figure 6
Parameters used to screen ligands based on drug likeliness.
Figure 7
Figure 7
Hydrogen bond interactions within the Protein and ligand 15 complex (a) 3D-image (b) 2D-image
Figure 8
Figure 8
(a) RMSD plot of protein, ligand and complex (b), RMSF plot of protein and ligand (c), RMSF of ligand.
Figure 9
Figure 9
A pathway showing role of Ror1in promoting tumor-cell growth, . During tumorous growth interleukin 6 (IL-6) binds with ILL6R1and GP130 and induces signal transducer activator of transcription 3 (STAT3) phosphorylation through the involvement of JAK proteins and upregulates Ror1 protein levels in a time- and dose-dependent manner by activating Ror1promoter activity. STAT3 also induces expression of Wnt5a that interacts with Ror1 to trigger PI3K/AKT through C-Src leading to activation of CREB that promotes tumor cell growth. Ror1 is synthesized in the nucleus and then it is transported to the cytoplasm where it inhibits the activity of ASK1, which follows a cascade that leads to apoptosis. At the same time, Ror1 activates S-src and PI3K, which in turn influences the CREB cycle to enhance expression of genes that enhance resistance to tumor cell apoptosis and/or promote tumor cell growth. Therefore, Ror1 functions to keep a balance between pro-survival PI3K-AKT and pro-apoptotic p38 signaling. [DNA Helix used in Fig. 9 is downloaded from https://pixabay.com/en/photos/?q=dna%20helix: All images on Pixabay website are released free of copyrights under Creative Commons CC0.]
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