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Identification of potential off-targets of chemotherapeutic agent Sorafenib: a molecular docking approach

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Sahrawat T. R., Chawla P.

International Letters of Natural Sciences

2016

tom 51

B-Raf is a multi- drug target serine/threonine protein kinase, involved in the transduction of mitogenic signals from the cell membrane to the nucleus. Mutated B-Raf causes overactive downstream signaling via MEK and ERK, leading to excessive cell proliferation and survival, independent of growth factors causing cancers such as Pancreatic carcinoma. A novel bi-aryl urea- Sorafenib, is a potent inhibitor of Raf-1 that has been approved for the treatment of a number of cancers including pancreatic cancer. The present investigation was designed to identify the potential off-targets of Sorafenib which could be responsible for its reported undesirable side effects. Molecular docking was used to test the efficacy of structural analogs of Sorafenib against B-Raf using FlexX and it was found that the analog with CID:10151557 had a high potency with minimum number of clashes, low lipophilic score and high match score, similar to Sorafenib. To identify the potential off-target/s of Sorafenib, macromolecular surface similarity detection software MEDIT SA MED-SuMo was used and the results obtained were validated through literature. The possible off-targets obtained belonged to the family of protein tyrosine kinases i.e. VEGFR-2, VEGFR-3, platelet-derived growth factor receptor beta, Flt-3, and c-KIT, each of which were docked with Sorafenib. Based on high docking scores and similarity with B-Raf for its binding site interacting residues, it was concluded that Vascular endothelial growth factor tyrosine kinase receptor (VEGFR) is a potential off-target of anti-cancer chemotherapeutic agent Sorafenib.

Time-dependent model to mimic acetylcholine induced vasodilatation in arterial smooth muscle cells

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Sahrawat T. R., Chatterjee D.

International Letters of Natural Sciences

2016

tom 52

Computational approaches for spatial modeling of dynamics of the intercellular distribution of molecules can parse, simplify, classify and organize the spatiotemporal richness of any biochemical pathway and demonstrate its impact on the cells function by simply coupling it with the downstream effecters. One such online system biology modeling package is Virtual cell that provides a unique open source software and it’s used for making mathematical models to simulate the cytoplasmic control of molecule that interact to produce certain cellular behavior. In our present study, a spatial model for time dependent acetylcholine induced relaxation of vascular endothelial cells lining the lumen of blood vessel that regulate the contractility of the arteries was generated. The time-dependent action of neurotransmitter acetylcholine for total time period for 1 second was studied on the endothelial cell at an interval of every 0.05 seconds. Such time simulated spatial models may be useful for testing and developing new hypotheses, interpretation of results and understand the dynamic behavior of cells.

Ograniczanie wyników

2 International Letters of Natural Sciences

2 Sahrawat T. R.

1 Chatterjee D.

1 Chawla P.

2 2016

Wyniki wyszukiwania

Identification of potential off-targets of chemotherapeutic agent Sorafenib: a molecular docking approach

Time-dependent model to mimic acetylcholine induced vasodilatation in arterial smooth muscle cells