期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 18, 期 5, 页码 2037-2048出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2010.01.020
关键词
HIV; HIV protease; Sulfoximine inhibitors; Transition state mimetic; Peptidomimetic; Asymmetric synthesis
资金
- Center for Drug Design at the University of Minnesota
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 nano-molar 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. (C) 2010 Elsevier Ltd. All rights reserved.
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