7l7o

Crystal structure of HCV NS3/4A D168A protease in complex with NR04-49

spinqualitylabelsall models 7l7o, resolution 1.72Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7l7o is a 1 chain structure with sequence from Hepacivirus C. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.72Å Ligands: EDO, SO4, XSY, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A8DG50_9HEPC Publication Abstract from PubMed The three pan-genotypic HCV NS3/4A protease inhibitors (PIs) currently in clinical use-grazoprevir, glecaprevir, and voxilaprevir-are quinoxaline-based P2-P4 macrocycles and thus exhibit similar resistance profiles. Using our quinoxaline-based P1-P3 macrocyclic lead compounds as an alternative chemical scaffold, we explored structure-activity relationships (SARs) at the P2 and P4 positions to develop pan-genotypic PIs that avoid drug resistance. A structure-guided strategy was used to design and synthesize two series of compounds with different P2 quinoxalines in combination with diverse P4 groups of varying sizes and shapes, with and without fluorine substitutions. Our SAR data and cocrystal structures revealed the interplay between the P2 and P4 groups, which influenced inhibitor binding and the overall resistance profile. Optimizing inhibitor interactions in the S4 pocket led to PIs with excellent antiviral activity against clinically relevant PI-resistant HCV variants and genotype 3, providing potential pan-genotypic inhibitors with improved resistance profiles. Discovery of Quinoxaline-Based P1-P3 Macrocyclic NS3/4A Protease Inhibitors with Potent Activity against Drug-Resistant Hepatitis C Virus Variants.,Nageswara Rao D, Zephyr J, Henes M, Chan ET, Matthew AN, Hedger AK, Conway HL, Saeed M, Newton A, Petropoulos CJ, Huang W, Kurt Yilmaz N, Schiffer CA, Ali A J Med Chem. 2021 Aug 26;64(16):11972-11989. doi: 10.1021/acs.jmedchem.1c00554., Epub 2021 Aug 18. PMID:34405680 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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