caa a22 4500 605512205 CHVBK 20210128100654.0 cr unu---uuuuu 210128e20151001xx s 000 0 eng 10.1007/s00894-015-2801-3 doi (NATIONALLICENCE)springer-10.1007/s00894-015-2801-3 Molecular docking and molecular dynamics studies reveal structural basis of inhibition and selectivity of inhibitors EGCG and OSU-03012 toward glucose regulated protein-78 (GRP78) overexpressed in glioblastoma [Elektronische Daten] [Rituparna Bhattacharjee, Arpita Devi, Seema Mishra] Glioblastoma (GBM), a malignant form of brain tumor, has a high mortality rate. GRP78, one of the HSP70 protein family members, is overexpressed in GBM. GRP78 is the key chaperone protein involved in the unfolded protein response. Upregulated GRP78 expression in cancer cells inhibits apoptosis and promotes chemoresistance. GRP78 has an ATPase domain, a substrate-binding domain, and a linker region. ATP-competitive inhibitors such as EGCG and OSU-03012 inhibit GRP78 activity and reduce its expression in GBM. However, there is a lack of structural data on the binding modes of these inhibitors to GRP78 ATPase domain. Further, the mode of selectivity of these inhibitors toward GRP78 also is unknown. Toward this end, molecular docking was performed with AutoDock Vina and confirmation obtained by docking using ROSIE. 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. 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 interactions with unique residues of GRP78 as compared with those of HSP70-1A provided the basis for selectivity. 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. OSU-03012 was predicted to bind to GRP78. 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. Energetic contribution of individual inhibitor-interacting residues showed that energy values of Ile61 and Glu293 were among the most negative. 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. Springer-Verlag Berlin Heidelberg, 2015 Glioblastoma nationallicence Glucose regulated protein 78 (GRP78) nationallicence Heat shock protein 70 nationallicence EGCG nationallicence OSU-03012 nationallicence Molecular docking nationallicence Molecular dynamics nationallicence Selectivity nationallicence Unfolded protein response (UPR) nationallicence MM-PBSA nationallicence GBM : Glioblastoma nationallicence GRP78 : Glucose regulated protein 78 nationallicence UPR : Unfolded protein response nationallicence HSP70-1A : Heat shock protein 70-1A nationallicence ATP : Adenosine triphosphate nationallicence ANP : Phosphoaminophosphonic acid-adenylate ester nationallicence EGCG : (−)-Epigallocatechingallate nationallicence PDB : Protein data bank nationallicence SDF : Structure data format nationallicence MSA : Multiple sequence alignment nationallicence MD : Molecular dynamics nationallicence ns : Nanoseconds nationallicence MM-PBSA : Molecular mechanics/Poisson−Boltzmann surface area nationallicence Bhattacharjee Rituparna Department of Biochemistry, School of Life Sciences, University of Hyderabad, 500046, Hyderabad, India aut Devi Arpita Department of Biochemistry, School of Life Sciences, University of Hyderabad, 500046, Hyderabad, India aut Mishra Seema Department of Biochemistry, School of Life Sciences, University of Hyderabad, 500046, Hyderabad, India aut Journal of Molecular Modeling Springer Berlin Heidelberg 21/10(2015-10-01), 1-17 1610-2940 21:10<1 2015 21 894 https://doi.org/10.1007/s00894-015-2801-3 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00894-015-2801-3 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Bhattacharjee Rituparna Department of Biochemistry, School of Life Sciences, University of Hyderabad, 500046, Hyderabad, India aut NATIONALLICENCE 700 1- Devi Arpita Department of Biochemistry, School of Life Sciences, University of Hyderabad, 500046, Hyderabad, India aut NATIONALLICENCE 700 1- Mishra Seema Department of Biochemistry, School of Life Sciences, University of Hyderabad, 500046, Hyderabad, India aut NATIONALLICENCE 773 0- Journal of Molecular Modeling Springer Berlin Heidelberg 21/10(2015-10-01), 1-17 1610-2940 21:10<1 2015 21 894