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Design, synthesis and biological evaluation of small molecule inhibitors of CD4-gp120 binding based on virtual screening |
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| Authors: | Lalonde Judith M Elban Mark A Courter Joel R Sugawara Akihiro Soeta Takahiro Madani Navid Princiotto Amy M Kwon Young Do Kwong Peter D Schön Arne Freire Ernesto Sodroski Joseph Smith Amos B |
| Affiliation: | a Department of Chemistry, Bryn Mawr College, Bryn Mawr, PA 19010, USA b Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA c Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA d Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA e Department of Biology, The Johns Hopkins University, Baltimore, MD 21218, USA |
| Abstract: | The low-molecular-weight compound JRC-II-191 inhibits infection of HIV-1 by blocking the binding of the HIV-1 envelope glycoprotein gp120 to the CD4 receptor and is therefore an important lead in the development of a potent viral entry inhibitor. Reported here is the use of two orthogonal screening methods, gold docking and ROCS shape-based similarity searching, to identify amine-building blocks that, when conjugated to the core scaffold, yield novel analogs that maintain similar affinity for gp120. Use of this computational approach to expand SAR produced analogs of equal inhibitory activity but with diverse capacity to enhance viral infection. The novel analogs provide additional lead scaffolds for the development of HIV-1 entry inhibitors that employ protein-ligand interactions in the vestibule of gp120 Phe 43 cavity. |
| Keywords: | HIV gp120 CD4 Entry inhibitor Virtual screening Docking Shape-based similarity |
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