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Herbal Metabolites as Potential Carbonic Anhydrase Inhibitors: Promising Compounds for Cancer and Metabolic Disorders
Ebrahim Yarmohammadi1, Maryam Khanjani1, Zahra Khamverdi1
1Department of Restorative Dentistry, School of Dentistry, Dental Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.
Background:
Human carbonic anhydrases (CAs) play a role in various pathological mechanisms by controlling intracellular and extracellular pH balance. Irregular expression and function of CAs have been associated with multiple human diseases, such as obesity, cancer, glaucoma, and epilepsy. In this work, we identify herbal compounds that are potential inhibitors of CA VI.
Methods:
We used the AutoDock tool to evaluate binding affinity between the CA VI active site and 79 metabolites derived from flavonoids, anthraquinones, or cinnamic acids. Compounds ranked at the top were chosen for molecular dynamics (MD) simulations. Interactions between the best CA VI inhibitors and residues within the CA VI active site were examined before and after MD analysis. Additionally, the effects of the most potent CA VI inhibitor on cell viability were ascertained in vitro through the 2,5-diphenyl-2H-tetrazolium bromide (MTT) assay.
Results:
Kaempferol 3-rutinoside-4-glucoside, orientin, kaempferol 3-rutinoside-7-sophoroside, cynarin, and chlorogenic acid were estimated to establish binding with the CA VI catalytic domain at the picomolar scale. The range of root mean square deviations for CA VI complexes with kaempferol 3-rutinoside-4-glucoside, aloe-emodin 8-glucoside, and cynarin was 1.37 to 2.05, 1.25 to 1.85, and 1.07 to 1.54 Å, respectively. The MTT assay results demonstrated that cynarin had a substantial effect on HCT-116 cell viability.
Conclusion:
This study identified several herbal compounds that could be potential drug candidates for inhibiting CA VI.
Insights
Researchers identified potent herbal inhibitors for carbonic anhydrase VI (CA VI), a key enzyme in pH balance and disease. These compounds show promise as potential therapeutic agents for CA VI-related conditions.
Area of Science:
- Biochemistry
- Pharmacology
- Medicinal Chemistry
Background:
- Human carbonic anhydrases (CAs) regulate pH balance, crucial for cellular function.
- Dysregulated CA activity is implicated in diseases like cancer, glaucoma, and epilepsy.
- Carbonic anhydrase VI (CA VI) is a specific target for therapeutic intervention.
Purpose of the Study:
- To identify novel herbal compounds that inhibit Carbonic Anhydrase VI (CA VI).
- To evaluate the binding affinity and molecular interactions of potential CA VI inhibitors.
- To assess the in vitro efficacy of identified inhibitors on cell viability.
Main Methods:
- Virtual screening using AutoDock to assess binding affinity of 79 herbal metabolites to the CA VI active site.
- Molecular dynamics (MD) simulations to analyze inhibitor-CA VI interactions.
- In vitro MTT assay to determine the effect of lead compounds on HCT-116 cell viability.
Main Results:
- Several flavonoids and phenolic acids, including kaempferol derivatives, orientin, cynarin, and chlorogenic acid, exhibited picomolar binding affinity to CA VI.
- MD simulations confirmed stable interactions between top inhibitors and the CA VI active site.
- Cynarin demonstrated a significant impact on HCT-116 cell viability in vitro.
Conclusions:
- Herbal compounds like cynarin are identified as potent inhibitors of CA VI.
- These findings suggest potential therapeutic applications for these natural products in treating CA VI-associated diseases.
- Further investigation into these compounds could lead to the development of new drug candidates.
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