Low Inhibiting Power of N···CO Based Peptidomimetic Compounds against HIV-1 Protease: Insights from a QM/MM Study

Abstract

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 ...