title: Design, synthesis and biological evaluation of small molecule inhibitors of CD4-gp120 binding based on virtual screening.
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.
authors.affiliation: Department of Chemistry, Bryn Mawr College, Bryn Mawr, PA 19010, USA. jlalonde@brynmawr.edu
authors.forename: Judith M
authors.initials: JM
authors.lastname: Lalonde
authors.forename: Mark A
authors.initials: MA
authors.lastname: Elban
authors.forename: Joel R
authors.initials: JR
authors.lastname: Courter
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sugawara
authors.forename: Takahiro
authors.initials: T
authors.lastname: Soeta
authors.forename: Navid
authors.initials: N
authors.lastname: Madani
authors.forename: Amy M
authors.initials: AM
authors.lastname: Princiotto
authors.forename: Young Do
authors.initials: YD
authors.lastname: Kwon
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.forename: Arne
authors.initials: A
authors.lastname: Schön
authors.forename: Ernesto
authors.initials: E
authors.lastname: Freire
authors.forename: Joseph
authors.initials: J
authors.lastname: Sodroski
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D015704:CD4 Antigens / Q000378:metabolism*; D015195:Drug Design; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008561:Membrane Fusion / Q000187:drug effects; D008958:Models, Molecular; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120