Design, asymmetric synthesis, and evaluation of pseudosymmetric sulfoximine inhibitors against HIV-1 protease

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Abstract

The HIV-1 protease is a validated drug target for the design of antiretroviral drugs to combat AIDS. We previously established the sulfoximine functionality as a valid transition state mimetic (TSM) in the HIV-1 protease inhibitors (PI) design and have identified a lead pseudosymmetric compound with nanomolar enzymatic inhibitory activity. Here, we report the asymmetric synthesis of this compound and its application in the synthesis of sulfoximine-based peptidomimetic HIV-1 protease inhibitors. Molecular modeling revealed the potential mode of binding of the sulfoximine inhibitor as a TSM. The predicted absolute binding free energies suggested similar inhibitory effect as observed in our enzymatic inhibitory studies.

Original languageEnglish (US)
Pages (from-to)2037-2048
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number5
DOIs
StatePublished - Mar 1 2010

Keywords

  • Asymmetric synthesis
  • HIV
  • HIV protease
  • Peptidomimetic
  • Sulfoximine inhibitors
  • Transition state mimetic

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