title: Structure-activity relationships in the binding of chemically derivatized CD4 to gp120 from human immunodeficiency virus.
abstract: The first step in HIV infection is the binding of the envelope glycoprotein gp120 to the host cell receptor CD4. An interfacial "Phe43 cavity" in gp120, adjacent to residue Phe43 of gp120-bound CD4, has been suggested as a potential target for therapeutic intervention. We designed a CD4 mutant (D1D2F43C) for site-specific coupling of compounds for screening against the cavity. Altogether, 81 cysteine-reactive compounds were designed, synthesized, and tested. Eight derivatives exceeded the affinity of native D1D2 for gp120. Structure-activity relationships (SAR) for derivatized CD4 binding to gp120 revealed significant plasticity of the Phe43 cavity and a narrow entrance. The primary contacts for compound recognition inside the cavity were found to be van der Waals interactions, whereas hydrophilic interactions were detected in the entrance. This first SAR on ligand binding to an interior cavity of gp120 may provide a starting point for structure-based assembly of small molecules targeting gp120-CD4 interaction.
authors.affiliation: Department of Pharmacology and Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Xie
authors.forename: Danny
authors.initials: D
authors.lastname: Ng
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Savinov
authors.forename: Barna
authors.initials: B
authors.lastname: Dey
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.forename: Richard
authors.initials: R
authors.lastname: Wyatt
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Hendrickson
mesh_terms: D000081:Acetamides / Q000737:chemistry; D001665:Binding Sites; D001667:Binding, Competitive; D015704:CD4 Antigens / Q000737:chemistry* / Q000235:genetics; D004220:Disulfides / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D015699:HIV Envelope Protein gp120 / Q000737:chemistry*; D015497:HIV-1 / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D013329:Structure-Activity Relationship