Molecular Dynamics Analysis of Inhibitor Binding Interactions in the <scp> <i>Vibrio cholerae</i> </scp> Respiratory Complex <scp>NQR</scp>

The sodium-pumping ubiquinone oxidoreductase sodium pumping quinone reductase (NQR) is an important enzyme in the respiratory chain of multiple pathogenic gram-negative bacteria. NQR has been proposed as a viable antibiotic target due to its importance in supporting energy-consuming reactions and its absence in human cells. In this study, molecular dynamics simulations were conducted to characterize the interactions between the ubiquinone binding pocket of Vibrio cholerae NQR with its substrate analogue ubiquinone-4 and three potent inhibitors: HQNO, aurachin-D42, and korormicin-A. Through interaction fingerprinting, distance calculations, and clustering analysis, important binding motifs for each of these ligands were identified. Subunit B residues K54, F137, E144, V145, V155, E157, G158, F159, and F160 were frequently identified as establishing either hydrogen bonding interactions or hydrophobic interactions with these three ligands. The findings of this in silico study are interpreted in view of mutagenesis analyses previously published in the literature. The elucidation of important binding interactions associated with the inhibitors is critical as it informs structure-activity relationships, which are essential for the development of novel antibiotics targeting NQR.