The Epidermal Growth Factor Receptor (EGFR) plays a pivotal role in 20-60% of cancer cases, including glioblastoma, lung adenocarcinoma, and head and neck squamous cell carcinoma, as reported in The Cancer Genome Atlas (TCGA) dataset. The present study employed an integrated in silico and experimental workflow to evaluate EGFR-targeted compounds from Terminalia arjuna. Drug-likeness and ADMET screening were performed, followed by molecular docking and 1000 ns molecular dynamics simulations. In vitro validation was conducted using cancer cell-based assays and network pharmacology to explore the molecular mechanisms associated with the identified compound. Screening shortlisted eight compounds from T. arjuna. Molecular docking identified Arjunaside C (-8.2 kcal/mol), Arjunapthanoloside (-7.7 kcal/mol), and Beta-sitosterol (-7.4 kcal/mol) as potential EGFR inhibitors compared to Erlotinib (-6.6 kcal/mol). Arjunapthanoloside formed more H-bonds and exhibited most stable interactions with EGFR. MD simulations at 1000 ns revealed lower RMSD, RMSF, SASA, and Rg values for the Arjunapthanoloside-EGFR complex, indicating enhanced stability. Direct binding validation was limited by the unavailability of purified Arjunapthanoloside; therefore, Arjuna extract was evaluated, which demonstrated potent cytotoxicity with an IC₅₀ of 9 µg/mL in H357 oral cancer cells. Flow cytometry confirmed apoptosis-mediated cell death by increased early- and late-apoptotic cell populations. Network pharmacology analysis further identified additional targets (MMP3, MMP7, MMP9, and HRAS) that are directly involved in various cancers. Overall, the findings provide new insights into the therapeutic potential of Arjunapthanoloside as a stable compound that interacts with EGFR from T. arjuna, highlighting its significance in EGFR-targeted anticancer research.
Shiwani Chahal, A. Debnath, Heena Jain et al.· Computational biology and ch...· 0 citations
Cotton Leaf Curl Disease (CLCuD)-associated begomoviruses (CABs) cause significant cotton crop losses worldwide. The genetic diversity and rapid evolution of CABs have significantly undermined efficacy of conventional and biotechnological interventions targeting viral genome, highlighting an urgent need for alternative strategies. Thus, this study aimed to devise a novel resistance strategy by targeting coat protein (CP) through peptide aptamers, which could halt infection very early. Phylogenetic analysis of 1322 CP sequences of CABs showed three interspecies clustering, indicating high conservation. Motif analysis through MEME further enriched this understanding by identifying 5, 4, and 10 conserved motifs in phylogenetic groups I, II, and III, respectively. Since nuclear localization signal (NLS) region has been considered crucial in CP- importin α interactions, NLS mapper tool was used to reveal conserved bipartite NLS (3KR-16KvRRR) in all CP variants. To identify interaction between CPs and importin α, 3D structures of 51 CP variants and importin α were modelled, refined, and validated using Alphafold, Galaxyrefine, and Procheck, respectively. Interestingly, besides NLS, docking studies identified additional conserved CP sites interacting with importin α, which laid foundation for designing peptide aptamers. A library of peptide aptamers was constructed using an R script and selected using PeptideRanker, PepDraw, molecular dockings and simulations. Two peptides demonstrated favorable predicted interactions with multiple major CP binding sites. These results provide preliminary computational insights into peptide-based targeting of viral proteins; however, their antiviral potential remains speculative and requires experimental validation through binding and functional assays before their utility in controlling CABs can be established.
