ABCB1 p.Thr627Glu
| Predicted by SNAP2: | A: N (72%), C: N (61%), D: N (66%), E: N (72%), F: N (61%), G: N (78%), H: N (93%), I: N (72%), K: N (66%), L: N (66%), M: N (87%), N: N (93%), P: N (57%), Q: N (82%), R: N (78%), S: N (87%), V: N (66%), W: N (53%), Y: N (72%), |
| Predicted by PROVEAN: | A: N, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: N, N: N, P: D, Q: D, R: D, S: N, V: D, W: D, Y: D, |
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[hide] In silico model for P-glycoprotein substrate predi... J Comput Aided Mol Des. 2013 Apr;27(4):347-63. doi: 10.1007/s10822-013-9650-x. Epub 2013 Apr 24. Prajapati R, Singh U, Patil A, Khomane KS, Bagul P, Bansal AK, Sangamwar AT
In silico model for P-glycoprotein substrate prediction: insights from molecular dynamics and in vitro studies.
J Comput Aided Mol Des. 2013 Apr;27(4):347-63. doi: 10.1007/s10822-013-9650-x. Epub 2013 Apr 24., [PMID:23612916]
Abstract [show]
P-glycoprotein (P-gp) is a plasma membrane efflux transporter belonging to ATP-binding cassette superfamily, responsible for multidrug resistance in tumor cells. Over-expression of P-gp in cancer cells limits the efficacy of many anticancer drugs. A clear understanding of P-gp substrate binding will be advantageous in early drug discovery process. However, substrate poly-specificity of P-gp is a limiting factor in rational drug design. In this investigation, we report a dynamic trans-membrane model of P-gp that accurately identified the substrate binding residues of known anticancer agents. The study included homology modeling of human P-gp based on the crystal structure of C. elegans P-gp, molecular docking, molecular dynamics analyses and binding free energy calculations. The model was further utilized to speculate substrate propensity of in-house anticancer compounds. The model demonstrated promising results with one anticancer compound (NSC745689). As per our observations, the molecule could be a potential lead for anticancer agents devoid of P-gp mediated multiple drug resistance. The in silico results were further validated experimentally using Caco-2 cell lines studies, where NSC745689 exhibited poor permeability (P app 1.03 +/- 0.16 x 10(-6) cm/s) and low efflux ratio of 0.26.
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No. Sentence Comment
197 The secondary structure prediction from HMMTOP and SAMT02 servers showed helical structure from Thr 627 to Glu 636 and Ser 658 to Arg 666 in linker region.
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ABCB1 p.Thr627Glu 23612916:197:96
status: NEW