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    Structural and thermodynamic basis for the binding of TMC114, a next-generation human immunodeficiency virus type 1 protease inhibitor

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    Authors
    King, Nancy M.
    Prabu-Jeyabalan, Moses
    Nalivaika, Ellen A.
    Wigerinck, Piet B. T. P.
    de Bethune, Marie-Pierre
    Schiffer, Celia A.
    UMass Chan Affiliations
    Department of Biochemistry and Molecular Pharmacology
    Document Type
    Journal Article
    Publication Date
    2004-10-14
    Keywords
    Binding Sites
    Carbamates
    Drug Resistance, Multiple, Viral
    HIV Protease Inhibitors
    HIV-1
    Humans
    Hydrogen Bonding
    Sulfonamides
    *Thermodynamics
    Life Sciences
    Medicine and Health Sciences
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    Abstract
    TMC114, a newly designed human immunodeficiency virus type 1 (HIV-1) protease inhibitor, is extremely potent against both wild-type (wt) and multidrug-resistant (MDR) viruses in vitro as well as in vivo. Although chemically similar to amprenavir (APV), the potency of TMC114 is substantially greater. To examine the basis for this potency, we solved crystal structures of TMC114 complexed with wt HIV-1 protease and TMC114 and APV complexed with an MDR (L63P, V82T, and I84V) protease variant. In addition, we determined the corresponding binding thermodynamics by isothermal titration calorimetry. TMC114 binds approximately 2 orders of magnitude more tightly to the wt enzyme (K(d) = 4.5 x 10(-12) M) than APV (K(d) = 3.9 x 10(-10) M). Our X-ray data (resolution ranging from 2.2 to 1.2 A) reveal strong interactions between the bis-tetrahydrofuranyl urethane moiety of TMC114 and main-chain atoms of D29 and D30. These interactions appear largely responsible for TMC114's very favorable binding enthalpy to the wt protease (-12.1 kcal/mol). However, TMC114 binding to the MDR HIV-1 protease is reduced by a factor of 13.3, whereas the APV binding constant is reduced only by a factor of 5.1. However, even with the reduction in binding affinity to the MDR HIV protease, TMC114 still binds with an affinity that is more than 1.5 orders of magnitude tighter than the first-generation inhibitors. Both APV and TMC114 fit predominantly within the substrate envelope, a property that may be associated with decreased susceptibility to drug-resistant mutations relative to that of first-generation inhibitors. Overall, TMC114's potency against MDR viruses is likely a combination of its extremely high affinity and close fit within the substrate envelope.
    Source
    J Virol. 2004 Nov;78(21):12012-21. Link to article on publisher's site
    DOI
    10.1128/JVI.78.21.12012-12021.2004
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/38665
    PubMed ID
    15479840
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1128/JVI.78.21.12012-12021.2004
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    UMass Chan Faculty and Researcher Publications
    Schiffer Lab Publications

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