article · International Journal of Biological Macromolecules
Researchers investigated the ability of natural terpenoid compounds extracted from Artemisia annua to inhibit carbonic anhydrase IX, an enzyme heavily present in oxygen-depleted tumour environments. Using laboratory assays, kinetic evaluations, and computational simulations, several compounds were tested against the enzyme target. Manool proved to be the most effective compound, displaying the strongest inhibitory potency, followed by labda-8(17),12-diene-15,16-dial. Both compounds showed a mixed mode of enzyme inhibition. Computational models confirmed that manool forms stable polar and hydrophobic bonds within the enzyme binding site, maintaining a resilient complex throughout dynamic testing. Preliminary pharmacokinetic analyses indicated favourable drug-like qualities for these terpenoids, including blood-brain barrier permeability for manool alongside possible metabolic interactions. These findings present manool as a promising candidate for further anticancer drug design targeting hypoxic tumours.
Hypoxic tumour environments often present significant barriers to effective cancer treatments. Because carbonic anhydrase IX is overexpressed in these conditions, targeting it offers a path to disrupt tumour survival. Identifying potent natural inhibitors such as manool provides new starting points for designing therapies that can precisely combat difficult-to-treat cancers.
This research provides early-stage preclinical evidence that could inform drug discovery programmes aimed at oncology therapeutics. Pharmaceutical companies and biotechnology developers focusing on hypoxic cancer targets are the primary prospective users. As the findings are based exclusively on in vitro testing and computational simulations, the candidate compounds remain at a very early stage of research, requiring extensive in vivo validation, toxicity assessments, and clinical trials before practical therapeutic application.
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This study evaluates the inhibitory potential of terpenoids isolated from Artemisia annua against carbonic anhydrase IX (CAIX), a crucial enzyme overexpressed in hypoxic tumor environments. Employing a multidisciplinary approach, we utilized in vitro assays, enzyme kinetics, molecular docking, and molecular dynamics (MD) simulations to comprehensively assess the efficacy of these compounds. Among the terpenoids tested, manool emerged as the most potent inhibitor, exhibiting the lowest IC<sub>50</sub> value of 160.2 ± 15.2 nM. This was followed by labda-8(17),12-diene-15,16-dial with an IC<sub>50</sub> of 297.9 ± 8.84 nM. Enzyme kinetics revealed a mixed inhibition mode for both compounds. Molecular docking aligned well with in vitro data, showing extensive polar and hydrophobic interactions within the CAIX binding site. Further insights were gained through 300 ns MD simulations, which highlighted the dynamic interactions and stability of these complexes. Manool demonstrated the most significant stabilization of CAIX, as evidenced by favorable RMSD, Rg, SASA profiles, and the strongest hydrogen bonding interactions. Additionally, MM/PBSA calculations confirmed manool's superior binding affinity. These findings underscore the therapeutic potential of manool as a potent CAIX inhibitor, providing a foundation for the development of effective anticancer agents targeting hypoxic tumor environments. ADMET analysis revealed favorable pharmacokinetic profiles for the terpenoids, with manool demonstrating high lipophilicity and BBB permeability, though potential CYP-mediated interactions were noted.
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DOI: 10.1016/j.ijbiomac.2024.136982
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