Alpha conotoxin-BuIA globular isomer is a competitive antagonist for oleoyl-L-alpha-lysophosphatidic acid binding to LPAR6; A molecular dynamics study

摘要

Lysophosphatidic acid receptor 6 (LPAR6) is a G-protein coupled receptor (GPCR) involved in hair development and cytoskeleton formation in mammals. Its proliferation is implicated in several forms of cancer including liver cancer, squamous cell carcinoma and metastatic prostate cancer. Current study emphasizes the isolation of competitive non-lipid and stable peptide antagonists for Lysophosphatidic acid ligand. A total of 148 conotoxin structures were characterized for their binding abilities against LPAR6. Subsequently, top 10 conotoxins were selected on the basis of binding energy values, residual contributions and conformational cluster saturations. BuIA (a member of Alpha- conotoxins family), contryphan-R and contryphan-Lo (Synthetic class) conotoxins, exhibiting efficient binding parameters were subjected to molecular dynamics simulation assays and topology analysis. We propose that BuIA might be a potent antagonist due to its predominant binding at the extracellular region of LPAR6. Current study provides a backbone for understanding structural and functional insights of LPAR6 and findings of this study may be helpful in designing novel therapeutic targets for the treatment of cancers caused by elevated LPAR6 expression.