Design, synthesis and antiviral activity of entry inhibitors that target the CD4-binding site of HIV-1
作者： Francesca Curreli , Spreeha Choudhury , Ilya Pyatkin , Victor P. Zagorodnikov , Anna Khulianova Bulay
DOI: 10.1021/JM3002247
关键词: Chemical synthesis 、 Linker 、 Chemistry 、 Phenyl group 、 Stereoisomerism 、 Combinatorial chemistry 、 Binding site 、 Ring (chemistry) 、 Stereochemistry 、 Structure–activity relationship 、 Small molecule
摘要: The CD4 binding site on HIV-1 gp120 has been validated as a drug target to prevent entry cells. Previously, we identified two small molecule inhibitors consisting of 2,2,6,6-tetramethylpiperidine ring linked by an oxalamide p-halide-substituted phenyl group, which this site, specifically, cavity termed "Phe43 cavity". Here use synthetic chemistry, functional assessment, and structure-based analysis explore variants each region these for improved antiviral properties. Alterations the group linker indicated that regions were close optimal in original lead compounds. Design series compounds, where tetramethylpiperidine was replaced with new scaffolds, led activity. These scaffolds provide insight into surface chemistry at entrance offer additional opportunities optimize further potential-next-generation therapeutics microbicides against HIV-1.
acs.org
osti.gov
sci-hub.se 参考文章(24)
Richard A. Friesner, Jay L. Banks, Robert B. Murphy, Thomas A. Halgren, Jasna J. Klicic, Daniel T. Mainz, Matthew P. Repasky, Eric H. Knoll, Mee Shelley, Jason K. Perry, David E. Shaw, Perry Francis, Peter S. Shenkin, Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. Journal of Medicinal Chemistry. ,vol. 47, pp. 1739- 1749 ,(2004) , 10.1021/JM0306430
R. Wyatt, The HIV-1 Envelope Glycoproteins: Fusogens, Antigens, and Immunogens Science. ,vol. 280, pp. 1884- 1888 ,(1998) , 10.1126/SCIENCE.280.5371.1884
Khandaker Siddiquee, Shumin Zhang, Wayne C. Guida, Michelle A. Blaskovich, Benjamin Greedy, Harshani R. Lawrence, M. L. Richard Yip, Richard Jove, Mark M. McLaughlin, Nicholas J. Lawrence, Said M. Sebti, James Turkson, Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity Proceedings of the National Academy of Sciences of the United States of America. ,vol. 104, pp. 7391- 7396 ,(2007) , 10.1073/PNAS.0609757104
Thomas A. Halgren, Robert B. Murphy, Richard A. Friesner, Hege S. Beard, Leah L. Frye, W. Thomas Pollard, Jay L. Banks, Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. Journal of Medicinal Chemistry. ,vol. 47, pp. 1750- 1759 ,(2004) , 10.1021/JM030644S
Loïc Martin, François Stricher, Dorothée Missé, Francesca Sironi, Martine Pugnière, Philippe Barthe, Rafael Prado-Gotor, Isabelle Freulon, Xavier Magne, Christian Roumestand, André Ménez, Paolo Lusso, Francisco Veas, Claudio Vita, Rational design of a CD4 mimic that inhibits HIV-1 entry and exposes cryptic neutralization epitopes Nature Biotechnology. ,vol. 21, pp. 71- 76 ,(2003) , 10.1038/NBT768
Scott D. Bembenek, John M. Keith, Michael A. Letavic, Richard Apodaca, Ann J. Barbier, Lisa Dvorak, Leah Aluisio, Kirsten L. Miller, Timothy W. Lovenberg, Nicholas I. Carruthers, Lead identification of acetylcholinesterase inhibitors–histamine H3 receptor antagonists from molecular modeling Bioorganic & Medicinal Chemistry. ,vol. 16, pp. 2968- 2973 ,(2008) , 10.1016/J.BMC.2007.12.048
Paul D. Lyne, Michelle L. Lamb, Jamal C. Saeh, Accurate prediction of the relative potencies of members of a series of kinase inhibitors using molecular docking and MM-GBSA scoring. Journal of Medicinal Chemistry. ,vol. 49, pp. 4805- 4808 ,(2006) , 10.1021/JM060522A
Krishna P. Ravindranathan, Valsan Mandiyan, Anil R. Ekkati, Jae H. Bae, Joseph Schlessinger, William L. Jorgensen, Discovery of Novel Fibroblast Growth Factor Receptor 1 Kinase Inhibitors by Structure-Based Virtual Screening Journal of Medicinal Chemistry. ,vol. 53, pp. 1662- 1672 ,(2010) , 10.1021/JM901386E
Navid Madani, Arne Schön, Amy M Princiotto, Judith M LaLonde, Joel R Courter, Takahiro Soeta, Danny Ng, Liping Wang, Evan T Brower, Shi-Hua Xiang, Young Do Kwon, Chih-chin Huang, Richard Wyatt, Peter D Kwong, Ernesto Freire, Amos B Smith, Joseph Sodroski, None, Small-Molecule CD4 Mimics Interact with a Highly Conserved Pocket on HIV-1 gp120 Structure. ,vol. 16, pp. 1689- 1701 ,(2008) , 10.1016/J.STR.2008.09.005
Shibo Jiang, Hong Lu, Shuwen Liu, Qian Zhao, Yuxian He, Asim K. Debnath, N-Substituted Pyrrole Derivatives as Novel Human Immunodeficiency Virus Type 1 Entry Inhibitors That Interfere with the gp41 Six-Helix Bundle Formation and Block Virus Fusion Antimicrobial Agents and Chemotherapy. ,vol. 48, pp. 4349- 4359 ,(2004) , 10.1128/AAC.48.11.4349-4359.2004