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Direct binding of microRNA-21 pre-element with Regorafenib: An alternative mechanism for anti-colorectal cancer chemotherapy?
- Source :
-
Journal of Molecular Graphics & Modelling . May2017, Vol. 73, p48-53. 6p. - Publication Year :
- 2017
-
Abstract
- The Regorafenib is a broad-spectrum kinase inhibitor that has been approved to treat colorectal cancer (CRC). However, evidences have shown that the agent is also implicated in drug interaction with microRNA-21 (miR-21), an oncogenic miRNA which plays a key role in resisting programmed cell death in CRC cells. Here, we supposed that, instead of kinase inhibition, Regorafenib can directly bind to and then stabilize miR-21 pre-element, thus preventing RNase Dicer-meditated cleavage of the pre-element to mature miR-21. In order to verify the notion, an in silico-in vitro integrated investigation of the direct intermolecular interaction between Regorafenib and miR-21 pre-element was performed by using active pocket identification, RNA–ligand docking, molecular dynamics (MD) simulation, binding energetic analysis, and fluorescence-based assay. It was revealed that the Regorafenib can bind at the major groove-like stem region of miR-21 pre-element through three geometrically satisfactory hydrogen bonds (H-bonds) as well as a number of hydrophobic forces and π-π stacking, conferring strong specificity and high stability to the RNA–ligand complex system ( K d = 0.73 μM). Separate inversion mutation of two base pairs (G6C, C12G) and (A13U, U4A) that are involved in the H-bonding can considerably impair the affinity of Regorafenib to miR-21 pre-element, with K d increase to 27 and 96 μM, respectively. All these supported that Regorafenib can directly bind to miR-21 pre-element at molecular level and the binding mode can be properly modeled by using the proposed integrated strategy. This study would provide a potential, alternative mechanism for anti-colorectal cancer chemotherapy with Regorafenib. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 10933263
- Volume :
- 73
- Database :
- Academic Search Index
- Journal :
- Journal of Molecular Graphics & Modelling
- Publication Type :
- Academic Journal
- Accession number :
- 123374304
- Full Text :
- https://doi.org/10.1016/j.jmgm.2017.02.004