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Identification of ligands that target the HCV-E2 binding site on CD81

Al Olaby, Reem and Azzazy, Hassan M. and Harris, Rodney and Chromy, Brett and Vielmetter, Jost and Balhorn, Rod (2013) Identification of ligands that target the HCV-E2 binding site on CD81. Journal of Computer-Aided Molecular Design, 27 (4). pp. 337-346. ISSN 0920-654X. doi:10.1007/s10822-013-9649-3.

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Hepatitis C is a global health problem. While many drug companies have active R&D efforts to develop new drugs for treating Hepatitis C virus (HCV), most target the viral enzymes. The HCV glycoprotein E2 has been shown to play an essential role in hepatocyte invasion by binding to CD81 and other cell surface receptors. This paper describes the use of AutoDock to identify ligand binding sites on the large extracellular loop of the open conformation of CD81 and to perform virtual screening runs to identify sets of small molecule ligands predicted to bind to two of these sites. The best sites selected by AutoLigand were located in regions identified by mutational studies to be the site of E2 binding. Thirty-six ligands predicted by AutoDock to bind to these sites were subsequently tested experimentally to determine if they bound to CD81-LEL. Binding assays conducted using surface Plasmon resonance revealed that 26 out of 36 (72 %) of the ligands bound in vitro to the recombinant CD81-LEL protein. Competition experiments performed using dual polarization interferometry showed that one of the ligands predicted to bind to the large cleft between the C and D helices was also effective in blocking E2 binding to CD81-LEL.

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Additional Information:© 2013 Springer Science+Business Media Dordrecht. Received: 27 December 2012; Accepted: 15 April 2013; Published online: 24 April 2013. This work was supported by The Nadhmi Auchi Fellowship, The American University in Cairo, awarded to R. Al Olaby. Computer time was provided by the National Biomedical Computational Resource at the University of California, San Diego. We would like to thank Dr. Arthur Olson’s molecular graphics laboratory at The Scripps Research Institute for supporting the AutoDock tutorial at Scripps Research Institute and providing assistance with AutoDock 4.2 and AutoDock Tools 1.5.6. We would also like to thank Dr. Shoshana Levy (Stanford University) for generously providing us with the human GST-CD81-LEL protein. Biacore support and instrument use was provided by the Protein Expression Center at Caltech. The ligands tested in this study were provided by the National Cancer Institute through its Developmental Therapeutics Program. Special thanks goes to Dr. David Tirrell (Tirrell lab-Caltech) and Nancy Aitken (Social Entrepreneur) for their great support.
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Nadhmi Auchi FellowshipUNSPECIFIED
American University in CairoUNSPECIFIED
Subject Keywords:Hepatitis C virus; HCV glycoprotein E2; AutoDock; CD81 receptor; Viral entry inhibitors; Dual polarization interferometry; Surface plasmon resonance
Issue or Number:4
Record Number:CaltechAUTHORS:20130725-101000069
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:39588
Deposited On:25 Jul 2013 20:08
Last Modified:09 Nov 2021 23:45

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