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.
Highlights
Ror[1], a member of Receptor tyrosine kinases (RTK) family, is an orphan-receptor tyrosine-kinase-like surface antigen, which is primarily expressed during the early stages of embryogenesis
Recent studies have reported the presence of natural humoral and cellular immunity against Ror[1] in chronic lymphocytic leukemia (CLL) patients[23] and expression of high levels of Ror[1] may promote cancer cell activation and survival enhancing disease progression in patients suffering from CLL24
We have investigated a truncated Ror[1] (‘t-receptor 1 (Ror1)’), as not much information regarding this isoform of Ror[1] (a 2373 bp transcript encoding 388 aa) is available. ‘t-Ror1’ is identical with the cytosolic, C-terminal region of Ror[1] but lacks the transmembrane and the entire extracellular domain
Summary
Ror[1], a member of RTK family, is an orphan-receptor tyrosine-kinase-like surface antigen, which is primarily expressed during the early stages of embryogenesis. Recent studies have reported the presence of natural humoral and cellular immunity against Ror[1] in chronic lymphocytic leukemia (CLL) patients[23] and expression of high levels of Ror[1] may promote cancer cell activation and survival enhancing disease progression in patients suffering from CLL24. Leukemia cells genetically engineered to promote anti-leukemia immune responses generated auto-antibodies specific for Ror[1] that did not react with non-tumor tissues showing that this receptor is specific to cancer cells[6]. Many studies support the notion that Ror[1] plays a functional role in promoting tumor cell growth and suggest that it may be a potential target for diagnosis and development of therapies against a variety of different human cancers[10, 28]. The major role of this protein is in cancer development and proliferation, and its role as a gateway for cancer indicates that the ligands can prove to be a remedy for the disease
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