Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455, USA.
Bioorg Med Chem. 2010 Mar 1;18(5):2037-48. doi: 10.1016/j.bmc.2010.01.020. Epub 2010 Jan 21.
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.
HIV-1 蛋白酶是设计抗艾滋病的抗逆转录病毒药物的有效药物靶点。我们之前已经确定亚砜亚胺官能团作为 HIV-1 蛋白酶抑制剂（PI）设计中的有效过渡态模拟物（TSM），并鉴定出具有纳摩尔酶抑制活性的先导拟肽化合物。在这里，我们报告了该化合物的不对称合成及其在基于亚砜亚胺的肽模拟 HIV-1 蛋白酶抑制剂合成中的应用。分子建模揭示了亚砜亚胺抑制剂作为 TSM 的潜在结合模式。预测的绝对结合自由能表明其抑制效果与我们的酶抑制研究中观察到的相似。
