Cancer Res 67(8):3496–3499īooth L, Cazanave SC, Hamid HA et al (2012) OSU-03012 suppresses GRP78/BiP expression that causes PERK-dependent increases in tumor cell killing. Lee AS (2007) GRP78 induction in cancer: therapeutic and prognostic implications. Li J, Lee AS (2006) Induction of GRP78/BiP and its role in cancer. Pyrko P, Schönthall AH, Hofman FM et al (2007) The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas. Mishra S (2014) CSNK1A1 and Gli2 as novel targets identified through an integrative analysis of gene expression data, protein-protein interaction and pathways networks in glioblastoma tumors: can these two be antagonistic proteins? Cancer Informat 13:93–108 Wang P, Dang Q, Zhang C et al (2013) Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Schwartzbaum JA, Fisher JL, Aldape KD et al (2006) Epidemiology and molecular pathology of glioma. (2014) The epidemiology of glioma in adults: a “state of the science” review. These studies are, to the best of our knowledge, the first studies characterizing EGCG and OSU-03012 interactions with GRP78 on a structural basis and provide a significant insight into their binding modes, selectivity, and structural stability. Energetic contribution of individual inhibitor-interacting residues showed that energy values of Ile61 and Glu293 were among the most negative. Analyses from MD runs showed tight binding and stability of complexes, and the highest number of hydrogen bonds during the trajectory runs were comparable to those found in the docking studies. OSU-03012 was predicted to bind to GRP78. It was found that the binding affinity and specificity/selectivity of EGCG toward GRP78 was higher than that toward HSP70-1A, and selectivity was even better than OSU-03012. The interactions with unique residues of GRP78 as compared with those of HSP70-1A provided the basis for selectivity. Important and unique amino acid residues of GRP78 such as Ile61, Glu293, Arg297, and Arg367 played a major role in the intermolecular interactions with these inhibitors. The stability and MM-PBSA binding energy of GRP78-inhibitor complexes as well as energetic contribution of individual residues was analyzed by 50 ns molecular dynamics run with GROMACS. MSA by ClustalW2 identified unique amino acid residues in the ATPase domain of GRP78 which were different from the residues present in other HSP70 proteins. Toward this end, molecular docking was performed with AutoDock Vina and confirmation obtained by docking using ROSIE. Further, the mode of selectivity of these inhibitors toward GRP78 also is unknown. However, there is a lack of structural data on the binding modes of these inhibitors to GRP78 ATPase domain. ATP-competitive inhibitors such as EGCG and OSU-03012 inhibit GRP78 activity and reduce its expression in GBM. GRP78 has an ATPase domain, a substrate-binding domain, and a linker region. Upregulated GRP78 expression in cancer cells inhibits apoptosis and promotes chemoresistance. GRP78 is the key chaperone protein involved in the unfolded protein response. GRP78, one of the HSP70 protein family members, is overexpressed in GBM. Glioblastoma (GBM), a malignant form of brain tumor, has a high mortality rate.
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