Virtual Screening for Novel Staphylococcus Aureus NorA Efflux Pump Inhibitors From Natural Products

Abstract

NorA is a member of the Major Facilitator Superfamily (MFS) drug efflux pumps that have been shown to mediate antibiotic resistance in Staphylococcus aureus (SA). In this study, QSAR analysis, virtual screening and molecular docking were implemented in an effort to discover novel SA NorA efflux pump inhibitors. Originally, a set of 47 structurally diverse compounds compiled from the literature was used to develop linear QSAR models and another set of 15 different compounds were chosen for extra validation. The final model which was estimated by statistical values for the full data set (n = 45, Q(2) = 0.80, RMSE = 0.20) and for the external test set (n = 15, R(2) = 0.60, |res|max = 0.75, |res|min = 0.02) was applied on the collection of 182 flavonoides and the traditional Chinese medicine (TCM) database to screen for novel NorA inhibitors. Finally, 33 lead compounds that met the Lipinski's rules of five/three and had good predicted pIC50 values from in silico screening process were employed to analyze the binding ability by docking studies on NorA homology model in place of its unavailable crystal structures at two active sites, the central channel and the Walker B.

Antibacterial activity of synthetic 1,3‐bis(aryloxy)propan‐2‐amines against Gram‐positive bacteria

“…shares hydrophobic interactions mainly with Leu62 and Leu236, but not limited to, with also a large number of hydrophobic side-chains surrounding both ring systems. Thai and collaborators by a comprehensive computational workflow have shown that SaNorA has a conserved large binding site within the channel offering more opportunities for binding sites than the one exploited here in this study (Thai et al, 2015).…”

Quantitative structure–activity relationship methods in the discovery and development of antibacterials

“…[70][71][72] Thai et al have developed a linear QSAR model to analyze a collection of 182 flavonoids and the Chinese Medicine Database searching for new S. aureus NorA pump inhibitors. 70 Similarly, Pereira et al developed a QSAR model for the search of antibacterial compounds in PubChem (1,804 compounds) and the AntiMarin Database (418 compounds). 71,72 In both cases, the virtual screening resulted in a group of theoretically active compounds that were later confirmed in the literature.…”

Drug Resistance in Bacteria, Fungi, Malaria, and Cancer

“…Physiological studies show that NorA transports structurally different antimicrobial agents like the fluoroquinolones (e.g., ciprofloxacin and norfloxacin), dyes (e.g., rhodamine and ethidium), and quaternary ammonium compounds (e.g., benzalkonium chloride and tetraphenylphosphonium) (Yoshida et al 1990;Kaatz et al 1993;Kaatz and Seo 1995). Recent primary studies of NorA have emphasized on efflux pump inhibitors of NorA (Holler et al 2012a, b;Roy et al 2013;Shiu et al 2013;Thai et al 2015) and regulation of NorA expression (Fournier et al 2000(Fournier et al , 2001Truong-Bolduc et al 2003Kosmidis et al 2010;Deng et al 2012), both topics of which are beyond the scope of this review but have been reviewed elsewhere (Zhang and Ma 2010;.…”