Introduction: Antimicrobial resistance is a significant public health challenge worldwide, especially in Gram-negative bacteria such as Pseudomonas aeruginosa. In recent years, P. aeruginosa has shown increasing multi- and pan-drug resistance, even to colistin, which is considered to be the last line of defence against resistant bacteria. Black cumin or Nigella sativa L., globally used as a spice, contains the bioactive compound thymoquinone, which is promising as a natural antibacterial agent due to its chemical properties. The high cost and complexity of developing new antibiotics is a significant obstacle and often leads to high attrition rates. However, computational chemistry is a promising approach that optimises the selection of candidates and supports the development of targeted antibacterial agents. This can speed up the discovery process and reduce costs in the ongoing fight against antimicrobial resistance.
Methods: The pharmacokinetic properties of thymoquinone and its pharmacological potential and bioavailability were computationally evaluated using the SwissADME tool. The topologies of the receptor proteins were analysed using the CASTp web server, and triple molecular docking simulations were performed using AutoDock Vina 1.1.2. Molecular visualisation and analysis were performed with PyMol and DS Visualizer.
Results: Thymoquinone fulfils all of Lipinski's rules of five criteria, which indicates favourable pharmacokinetic properties for potential therapeutic use. Molecular docking simulations show a strong binding affinity to the MvfR protein in P. aeruginosa, which is an important regulator of virulence and quorum sensing. Seven (out of nine) models showed consistent interactions with a root mean square deviation (RMSD) of less than 5 Å, often involving the amino acid Ile236.
Conclusions: Computational chemistry can enhance the development of new antibiotics. Thymoquinone shows favourable pharmacokinetics and a strong binding affinity to the MvfR protein in P. aeruginosa. Thymoquinone shows potential as an antimicrobial agent against P. aeruginosa, but further in vitro and in vivo tests, including toxicological studies, are needed to evaluate its cytotoxicity.
