Low Inhibiting Power of N···CO Based Peptidomimetic Compounds against HIV-1 Protease: Insights from a QM/MM Study
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- 作者：Julian Garrec ; Michele Cascella ; Ursula Rothlisberger ; Paul Fleurat-Lessard
- 刊名：Journal of Chemical Theory and Computation
- 出版年：2010
- 出版时间：April 13, 2010
- 年：2010
- 卷：6
- 期：4
- 页码：1369-1379
- 全文大小：296K
- 年卷期：v.6,no.4(April 13, 2010)
- ISSN：1549-9626
文摘
Recently, Hasserodt et al. proposed new HIV-1 drug candidates based on a weak N···CO interaction, designed to be a close transition state analog (Gautier et al. Bioorg. Med. Chem. 2006, 14, 3835−3847; Waibel et al. J. Bioorg. Med. Chem. 2009, 17, 3671−3679). They suggested that further improvement of these compounds could take advantage of computational approaches. In the present work, we propose an atomistic model based on a QM/MM description of the N···CO core embedded in an amino-aldehyde peptidic inhibitor. We focus on the existence of the N···CO interaction in the aqueous and enzymatic media. We show that the N···CO bond holds in water, while in the protein, there is a competition between the formation of the weak N···CO bond and the conservation of the hydrogen bond network around the structural water molecule W301 that is known to be crucial for the binding of both substrates and inhibitors. This competition hampers the inhibitor to provide strong stabilizing interactions with all the key parts of the protein at the same time. Our calculations indicate that this competition we observed in peptidic compounds might be avoided by the proper design of nonpeptidic ones, following a similar strategy to that for cyclic urea derivatives and the FDA approved drug Tipranavir. Hence, our results encourage further development of the nonpeptidic hydrazino-urea derivatives suggested recently by Hasserodt et al.