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Heliotropium ramosissimum metabolic profiling, in silico and in vitro evaluation with potent selective cytotoxicity against colorectal carcinoma.

ABSTRACT: Heliotropium is a genus of the Boraginaceae family. Its members are used in many traditional and folklore medicines to treat several ailments. Despite this widespread usage, only a few evidence-based scientific studies investigated and identified its phytoconstituents. Herein, we documented the chemical profile of the Heliotropium ramosissimum methanolic extract using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-ESI-MS/MS) and assessed its antioxidant and cytotoxic effects. The methanolic extract exhibited high phenolic content (179.74 ± 0.58 µg/mL) and high flavonoid content (53.18 ± 0.60 µg/mL). The GC-MS analysis of the lipoidal matter allowed us to identify 41 compounds with high percentages of 1,2-benzenedicarboxylic acid, bis(2-methoxyethyl) ester (23.91%), and 6,10,14-trimethylpentadecan-2-one (18.74%). Thirty-two phytomolecules were tentatively identified from the methanolic extract of H. ramosissimum using LC-MS/MS. These compounds belonged to several phytochemical classes such as phenolic acids, alkaloids, coumarins, and flavonoids. Furthermore, we assessed the antioxidant activity of the methanolic extract by DPPH assay and oxygen radical absorbance capacity assay, which yielded IC₅₀ values of 414.30 µg/mL and 170.03 ± 44.40 µM TE/equivalent, respectively. We also assessed the cytotoxicity of the methanolic extract on seven different cell lines; Colo-205, A-375, HeLa, HepG-2, H-460, and OEC showed that it selectively killed cancer cells with particularly potent cytotoxicity against Colo-205 without affecting normal cells. Further studies revealed that the extract induced apoptosis and/or necrosis on Colo-205 cell line at an IC₅₀ of 18.60 µg/mL. Finally, we conducted molecular docking on the LC-ESI-MS/MS-identified compounds against colon cancer antigen 10 to find potentially cytotoxic compounds. Binding score energy analysis showed that isochlorogenic acid and orientin had the highest affinity for the colon cancer antigen 10 protein, with binding scores of (- 13.2001) and (- 13.5655) kcal/mol, respectively. These findings suggest that Heliotropium ramosissimum contains potent therapeutic candidates for colorectal cancer treatment.

SUBMITTER: Fayed MAA

PROVIDER: S-EPMC9307647 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundColorectal cancer is common to both sexes; third in terms of morbidity and second in terms of mortality, accounting for 10% and 9.2% of cancer cases in men and women globally. Although drugs such as bevacizumab, Camptosar, and cetuximab are being used to manage colorectal cancer, the efficacy of the drugs has been reported to vary from patient to patient. These drugs have also been reported to have varying degrees of side effects; thus, the need for novel drug therapies with better efficacy and lesser side effects. In silico drugs design methods provide a faster and cost-effect method for lead identification and optimization. The aim of this study, therefore, was to design novel imidazol-5-ones via in silico design methods.ResultsA QSAR model was built using the genetic function algorithm method to model the cytotoxicity of the compounds against the HCT116 colorectal cancer cell line. The built model had statistical parameters; R2 = 0.7397, R2adj = 0.6712, Q2cv = 0.5547, and R2ext. = 0.7202 and revealed the cytotoxic activity of the compounds to be dependent on the molecular descriptors nS, GATS5s, VR1_Dze, ETA_dBetaP, and L3i. These molecular descriptors were poorly correlated (VIF < 4.0) and made unique contributions to the built model. The model was used to design a novel set of derivatives via the ligand-based drug design approach. Compounds e, h, j, and l showed significantly better cytotoxicity (IC50 < 5.0 μM) compared to the template. The interaction of the compounds with the CDK2 enzyme (PDB ID: 6GUE) was investigated via molecular docking study. The compounds were potent inhibitors of the enzyme having binding affinity of range -10.8 to -11.0 kcal/mol and primarily formed hydrogen bond interaction with lysine, aspartic acid, leucine, and histidine amino acid residues of the enzyme.ConclusionThe QSAR model built was stable, robust, and had a good predicting ability. Thus, predictions made by the model were reliably employed in further in silico studies. The compounds designed were more active than the template and showed better inhibition of the CDK2 enzyme compared to the standard drugs sorafenib and kenpaullone.

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Heliotropium ramosissimum metabolic profiling, in silico and in vitro evaluation with potent selective cytotoxicity against colorectal carcinoma.

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