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 language | English (US) |
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Pages (from-to) | 2037-2048 |
Number of pages | 12 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 18 |
Issue number | 5 |
DOIs | |
State | Published - Mar 1 2010 |
Keywords
- Asymmetric synthesis
- HIV
- HIV protease
- Peptidomimetic
- Sulfoximine inhibitors
- Transition state mimetic