COMPARATIVE MOLECULAR DOCKING AND ADMET PREDICTION OF SELECTED PLANT ALKALOIDS AS POTENTIAL INHIBITORS OF Staphylococcus aureus NorA EFFLUX PUMP
DESMOND CHUKWUDI IKEM1,*
- Plant Science and Biotechnology, Department of Biological Sciences, University of Delta, Agbor.
Afr. J Pharm Res Dev; Volume 17(3): 259-268 ; 2025
ABSTRACT
Efflux pumps are a major mechanism of multidrug resistance (MDR) in Staphylococcus aureus. These pumps actively extrude antibiotics, thereby reducing their efficacy. Plants are becoming increasingly recognized as very important sources of medicines due to their diverse phytochemicals, including alkaloids. Alkaloids and other phytochemicals are investigated as potential efflux pump inhibitors (EPIs). EPIs can be used to potentiate the activity of antibiotics via inhibition of the efflux pump through physical blockade of the NorA’s anchoring site for substrates (such as antibiotics), thereby preventing the efflux of the administered antibiotics. Currently, there is no known clinically approved efflux pump inhibitor. In this study, ten alkaloids were selected to evaluate their potential as efflux pump inhibitors (EPIs). Docking was performed using AutoDock Vina. Binding affinities among the ten compounds ranged from -8.1 to – 10.8 kcal/mol. Reserpine (a well-established reference inhibitor of S. aureus efflux pump), used as a control, exhibited a binding affinity of -9.5 kcal/mol. Three ligands, including toxiferine (the most active alkaloid; -10.8kcal/mol), exhibited a higher binding affinity than reserpine. Docking analysis was guided by key functional residues identified via supervised molecular dynamics (SuMD) of ciprofloxacin to the primary pocket of S. aureus NorA. Two-dimensional interaction profiling revealed that high-affinity binding was associated with extensive interaction coverage and formation of strong, specific non-covalent interactions with key functional residues of the NorA substrate-binding pocket. Consequently, toxiferine interacted with all seven of the SuMD-identified hotspot residues, with some of these interactions being conspicuously strong compared with other alkaloids. Conversely, piperine (the least active alkaloid; -8.1 kcal/mol) interacted with only one of the SuMD hotspot residues. ADMET analysis was performed using SwissADME to assess the pharmacokinetic properties of all the tested ligands. The alkaloids exhibited a spectrum of pharmacokinetic properties. Physicochemical and drug-likeness profiling of toxiferine revealed that it violated Lipinski’s molecular weight threshold (500 g/mol) and showed very low cLogP (-1.22), which suggests low passive absorption. Remarkably, it maintained low CYP450-mediated metabolic liability. Overall, it shows potential as an inhibitor or lead scaffold for the design of novel EPIs. In vitro and in vivo assays are required to validate the efficacy and safety of toxiferine and other tested alkaloids.
Keywords: Staphylococcus aureus, alkaloids, multi-drug resistance, efflux pump, molecular docking,
ADMET
Email of correspondence: peter.desmonddilo@gmail.com,;
https://doi.org/10.59493/ajopred/2025.3.2 ISSN: 0794-800X (print); 1596-2431 (online)