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AuthorThirumal Kumar, D
AuthorIyer, Sharada
AuthorChristy, J Priyadharshini
AuthorSiva, R
AuthorTayubi, Iftikhar Aslam
AuthorGeorge Priya Doss, C
AuthorZayed, Hatem
Available date2019-01-24T07:23:50Z
Publication Date2019-01-01
Publication NameAdvances in Protein Chemistry and Structural Biologyen_US
Identifierhttp://dx.doi.org/10.1016/bs.apcsb.2018.10.002
CitationThirumal Kumar D, Iyer S, Christy JP, Siva R, Tayubi IA, George Priya Doss C, Zayed H. A comparative computational approach toward pharmacological chaperones (NN-DNJ and ambroxol) on N370S and L444P mutations causing Gaucher's disease. Adv Protein Chem Struct Biol. 2019;114:315-339. doi: 10.1016/bs.apcsb.2018.10.002.
ISSN1876-1623
URIhttp://hdl.handle.net/10576/11284
AbstractGaucher's disease (GD) is the most commonly known lysosomal disorder that occurs due to mutations in the β-glucocerebrosidase (GBA) protein. Our previous findings (Thirumal Kumar, Eldous, Mahgoub, George Priya Doss, Zayed, 2018) and other reports concluded that the mutations N370S and L444P are the most significant mutations that could cause disruptions in protein stability and structure. These disruptions lead to protein misfolding and result in a diseased condition. Enzyme Replacement Therapy (ERT) and Pharmacological chaperone therapy (PCT) are currently used to treat GD caused by mutations in the GBA protein. The extreme disparity in cost between ERT and chaperone therapy, shifted the attention toward chaperone therapy. The most common chaperones in the market and trial phases to treat GD are Isofagomine, Miglustat, Eliglustat, NN-DNJ, and Ambroxol. In the era of personalized medicine, it is often necessary to understand the drug likeliness of each chaperone. In this context, the present study utilized molecular docking analysis to understand the interaction behavior of the chaperone toward the native and the two mutants N370S and L444P. The molecular dynamics simulation analyses performed on chaperones (NN-DNJ and Ambroxol) interaction showed that the chaperone NN-DNJ possesses better affinity toward the protein with N370S mutation whereas chaperone Ambroxol showed better activity against both the significant mutations (N370S and L444P). This study is expected to serve as a platform for drug repurposing.
Languageen
PublisherElsevier
SubjectAmbroxol
SubjectGaucher's disease
SubjectL444P
SubjectMolecular docking
SubjectMolecular dynamics
SubjectN370S
SubjectNN-DNJ
TitleA comparative computational approach toward pharmacological chaperones (NN-DNJ and ambroxol) on N370S and L444P mutations causing Gaucher's disease.
TypeBook chapter
Pagination315-339
Issue Number114
ESSN1876-1631


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