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

• Autorzy: Sahrawat T.R. , Chawla P.
• Języki publikacji: EN

Abstrakty

EN

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.

Słowa kluczowe

EN

chemotherapeutic agent; Pancreatic carcinoma; sorafenib; molecular docking; tyrosine kinase; vascular endothelial growth factor; side effect

• Wydawca: -
• Czasopismo: International Letters of Natural Sciences
• Rocznik: 2016
• Tom: 51
• Opis fizyczny: p.51-57,fig.,ref.

Twórcy

autor

Sahrawat T.R.

• Centre for System Biology and Bioinformatics, UIEAST, Panjab University, Chandigarh, India

autor

Chawla P.

• Centre for System Biology and Bioinformatics, UIEAST, Panjab University, Chandigarh, India

Bibliografia

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Identyfikatory

DOI

10.18052/www.scipress.com/ILNS.51.51