Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 50, Issue 20, Pages 4898-4908Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm070564e
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Funding
- Intramural NIH HHS [Z99 AI999999] Funding Source: Medline
- NIGMS NIH HHS [P01 GM056550, P01-GM 056550] Funding Source: Medline
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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 gp 120. Structure-activity relationships (SAR) for derivatized CD4 binding to gp 120 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 gp 120 may provide a starting point for structure-based assembly of small molecules targeting gp120-CD4 interaction.
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