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Highly potent HIV-1 protease inhibitors with novel tricyclic P2 ligands: design, synthesis, and protein-ligand X-ray studies.

ABSTRACT: The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in the protease active site. Inhibitors 16a and 16f showed excellent enzyme inhibitory and antiviral activity, although the incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors 16a and 16f maintained activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 16a-bound HIV-1 protease revealed important molecular insights into the ligand-binding site interactions, which may account for the inhibitor's potent antiviral activity and excellent resistance profiles.

SUBMITTER: Ghosh AK

PROVIDER: S-EPMC3800042 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Highly potent HIV-1 protease inhibitors with novel tricyclic P2 ligands: design, synthesis, and protein-ligand X-ray studies.

Ghosh Arun K AK Parham Garth L GL Martyr Cuthbert D CD Nyalapatla Prasanth R PR Osswald Heather L HL Agniswamy Johnson J Wang Yuan-Fang YF Amano Masayuki M Weber Irene T IT Mitsuya Hiroaki H

Journal of medicinal chemistry 20130815 17

The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in the protease active site. Inhibitors 16a and 16f showed excellent enzyme inhibitory and antiviral activity, although the incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors 16a and 16f maintain ...[more]

PMID: 23947685

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Highly potent HIV-1 protease inhibitors with novel tricyclic P2 ligands: design, synthesis, and protein-ligand X-ray studies.

Publications

Highly potent HIV-1 protease inhibitors with novel tricyclic P2 ligands: design, synthesis, and protein-ligand X-ray studies.

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