Novel targets for treating cancer and inflammatory disorders: A disintegrin-metalloprotease-10 and cyclooxygenase-2 feedback loop modulated by Aconitum heterophyllum leaf biomarkers with computational biology

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BACKGROUND: Since antiquity, humans have relied on diverse natural products species for disease treatment and health enhancement. Aconitum is comprised of pharmacologically active biomarkers and offers a tempting prospect for medical research. This study addressed the metabolic profile, pharmacological assay, pharmacokinetics, molecular docking, and dynamics simulations (MDS). METHOD: Metabolic profiling of AHL was conducted by mass spectrometry analysis. In vitro MTT assay were employed to assess anticancer potential, while in vivo animal models were utilized to investigate the inflammation potential. Molecular docking was performed against COX-2 and ADAM10 enzymes. MOE and ADMET tool were employed for bioinformatics. Docking complexes of miraxanthin V with ADAM10 and COX2 were subjected to 60 PS molecular dynamics simulations (10 PS equilibration, 50 PS production) using the MMFF94x force field and NPA algorithm at 300 K. RESULTS: A total of 141 metabolites were identified. Of these, 86 metabolites were detected in the methanol extract (58/ESI+ and 28/ESI-). In contrast, the n-hexane had 55 metabolites (34/ESI+ and 21/ESI-). The detected metabolites belong to various classes, 14-alkaloids, 15-phenolics, 6-flavonoids, 17-terpenoids, 2-quinolines, 5- lignans/coumarins, 4-steroids/glycosides, and 55 other organic, while 23 unknown peaks were noticed. In vitro assay revealed significant anticancer activity against H9c2 and MDCK cells, supported by molecular studies. The anti-inflammatory and antinociceptive effects, demonstrated significant dose dependency. Molecular docking recognized potent inhibition of L1, L2, L3, and L4 against COX-2, while L1, L2, L4, and L7 against ADAM10. A promising oral bioavailability was indicated by L1, L2, L4, and L6, signifies as drugs candidate. Both complexes showed excellent stability (temperature ∼298.8 K, no unbinding). COX2 exhibited 2-fold superior binding rigidity (0.091 % vs. 0.19 % energy variation), indicating preferential selectivity and COX2-selective inhibitor potential. CONCLUSION: The results indicated potential anticancer, anti-inflammatory and analgesic effect. AHL marked remarkable efficacy against cancer and inflammation diseases, and may be suggested as a traditional medicine after further enhanced investigations. These findings will be helpful in chemotaxonomy and further insights into the metabolites of this plant will improve research in pharmacology.

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