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    Structural and Thermodynamic Effects of Macrocyclization in HCV NS3/4A Inhibitor MK-5172

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    Authors
    Soumana, Djade I.
    Yilmaz, Nese Kurt
    Prachanronarong, Kristina L.
    Aydin, Cihan
    Ali, Akbar
    Schiffer, Celia A.
    UMass Chan Affiliations
    Department of Biochemistry and Molecular Pharmacology
    Document Type
    Journal Article
    Publication Date
    2016-04-15
    Keywords
    Biochemistry
    Medicinal Chemistry and Pharmaceutics
    Medicinal-Pharmaceutical Chemistry
    Molecular Biology
    Structural Biology
    Virology
    
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    Link to Full Text
    http://dx.doi.org/10.1021/acschembio.5b00647
    Abstract
    Recent advances in direct-acting antivirals against Hepatitis C Virus (HCV) have led to the development of potent inhibitors, including MK-5172, that target the viral NS3/4A protease with relatively low susceptibility to resistance. MK-5172 has a P2-P4 macrocycle and a unique binding mode among current protease inhibitors where the P2 quinoxaline packs against the catalytic residues H57 and D81. However, the effect of macrocyclization on this binding mode is not clear, as is the relation between macrocyclization, thermodynamic stabilization, and susceptibility to the resistance mutation A156T. We have determined high-resolution crystal structures of linear and P1-P3 macrocyclic analogs of MK-5172 bound to WT and A156T protease and compared these structures, their molecular dynamics and experimental binding thermodynamics to the parent compound. We find that the "unique" binding mode of MK-5172 is conserved even when the P2-P4 macrocycle is removed or replaced with a P1-P3 macrocycle. While beneficial to decreasing the entropic penalty associated with binding, the constraint exerted by the P2-P4 macrocycle prevents efficient rearrangement to accommodate the A156T mutation, a deficit alleviated in the linear and P1-P3 analogs. Design of macrocyclic inhibitors against NS3/4A needs to achieve the best balance between exerting optimal conformational constraint for enhancing potency, fitting within the substrate envelope and allowing adaptability to be robust against resistance mutations.
    Source
    ACS Chem Biol. 2016 Apr 15;11(4):900-9. doi: 10.1021/acschembio.5b00647. Epub 2016 Jan 6. Link to article on publisher's site
    DOI
    10.1021/acschembio.5b00647
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/48873
    PubMed ID
    26682473
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1021/acschembio.5b00647
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