Abstract
Pancreatic cancer is the seventh most prevalent cause of mortality globally. Since time immemorial, plant-derived products have been in use as therapeutic agents due to the existence of biologically active molecules called secondary metabolites. Flavonoids obtained from plants participate in cell cycle arrest, induce autophagy and apoptosis, and decrease oxidative stress in pancreatic cancer. The present study involves network pharmacology-based study of the methanolic leaf extract of Trema orientalis (MLETO) Linn. From the high-resolution mass spectrometry (HRMS) analysis, 21 nucleated flavonoids were screened out, of which only apigeniflavan was selected for further studies because it followed Lipinski’s rule and showed no toxicity. The pharmacokinetics and physiochemical characteristics of apigeniflavan were performed using the online web servers pkCSM, Swiss ADME, and ProTox-II. This is the first in silico study to report the efficiency of apigeniflavan in pancreatic cancer treatment. The targets of apigeniflavan were fetched from SwissTargetPrediction database. The targets of pancreatic cancer were retrieved from DisGeNET and GeneCards. The protein–protein interaction of the common genes using Cytoscape yielded the top five hub genes: KDR, VEGFA, AKT1, SRC, and ESR1. Upon molecular docking, the lowest binding energies corresponded to best docking score which indicated the highest protein–ligand affinity. Kyoto Encyclopaedia of Genes and Genomes (KEGG) database was employed to see the involvement of hub genes in pathways related to pancreatic cancer. The following, pancreatic cancer pathway, MAPK, VEGF, PI3K–Akt, and ErbB signaling pathways, were found to be significant. Our results indicate the involvement of the hub genes in tumor growth, invasion and proliferation in the above-mentioned pathways, and therefore necessitating their downregulation. Moreover, apigeniflavan can flourish as a promising drug for the treatment of pancreatic cancer in future.
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Abbreviations
- HRMS:
-
High-resolution mass spectrometry
- MLETO:
-
Methanolic leaf extract of Trema orientalis
- KEGG:
-
Kyoto encyclopaedia of genes and genomes
- ROS:
-
Reactive oxygen species
- PPI:
-
Protein–protein interaction
- ADME:
-
Absorption, distribution, metabolism, and excretion
- HBD:
-
Hydrogen bond donor
- HBA:
-
Hydrogen bond acceptor
- TPSA:
-
Topological polar surface area
- DL:
-
Druglikeness
- MR:
-
Molar refractivity
- HIA:
-
Human intestinal absorption
- BBB:
-
Blood–brain barrier
- CNS:
-
Central nervous system
- OCT2:
-
Organic cation transporter 2 substrate
- CYP2D6:
-
CYP2D6 Cytochrome P450 2D6
- CYP3A4:
-
Cytochrome P450 3A4
- hERG:
-
Human ether-a-go-go related gene
- LOAEL:
-
Lowest-observed adverse-effect level
- LD50:
-
Lethal dose 50
- TCMSP:
-
Traditional Chinese medicine systems pharmacology database and analysis platform
- STRING:
-
Search tool for the retrieval of interacting genes/proteins
- GO:
-
Gene ontology
- DAVID:
-
Database for annotation, visualization and integrated discovery
- GEPIA:
-
Gene expression profiling interactive analysis
- MW:
-
Molecular weight
- ADMET:
-
Absorption, distribution, metabolism, excretion, and toxicity
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The author, Richa Das, gratefully acknowledges the Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, and Parul Institute of Applied Science, Parul University, for their immense support.
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SKM and KNT: developed the concept and design of the work. RD, SA, PK, and AKS: data collection, analysis, and interpretation of results. IB, AKT, and KNT: revision of manuscript. PKS: fractionation.
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Das, R., Agrawal, S., Kumar, P. et al. Network pharmacology of apigeniflavan: a novel bioactive compound of Trema orientalis Linn. in the treatment of pancreatic cancer through bioinformatics approaches. 3 Biotech 13, 160 (2023). https://doi.org/10.1007/s13205-023-03570-7
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DOI: https://doi.org/10.1007/s13205-023-03570-7