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A. Jamil

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Open access Aug 2026

The Activity of Antimicrobial Peptides (AMPs) Identified Via an Integrated in Silico and Pilot in Vitro Screening Approach Towards ESKAPE Pathogens.

Antimicrobial resistance (AMR), driven largely by ESKAPE(E) pathogens, represents a critical global health challenge. The increasing prevalence of multidrug-resistant (MDR) bacteria and the declining effectiveness of conventional antibiotics have created an urgent need for innovative therapeutic agents with novel mechanisms of action. In this study, we aimed to establish a stability-centric computational discovery pipeline to identify and characterize novel antimicrobial peptides (AMPs) with potent and selective bactericidal activity against ESKAPE pathogens, and to validate the lead candidates through experimental in vitro assays. A library of approximately 3,000 AMPs was retrieved from public databases and subjected to in silico screening for physicochemical properties and predicted toxicity. Following filtration, 200 peptides were selected as ligands for molecular docking against essential target proteins from ESKAPE pathogens. Based on docking scores, binding pocket occupancy, and ligand-protein interaction, the top 10 peptides against each bacterium were shortlisted. The four top consensus hits of Vespid Chemotactic Peptide VT1 (VCP-VT1), Taromycin A, CN-AMP1, and Alliumin were selected based on their superior inhibitory profiles. Subsequent peptide-protein docking analyses confirmed their binding modes and interaction patterns. These four candidates were advanced to peptide-protein interaction profiling, followed by pilot in vitro minimum bactericidal concentration (MBC) determination and cytotoxicity assessment on a mammalian cell line. Hierarchical consensus scoring identified VCP-VT1, Taromycin A, CN-AMP1, and Alliumin as the top-ranked binding AMPs. VCP-VT1 was the most potent peptide in preliminary MBC assays, with modest activity against Gram-positive Enterococcus faecalis, Enterococcus faecium and Staphylococcus aureus, and Gram-negative Acinetobacter baumannii and Pseudomonas aeruginosa (MBC50 of 50 µM, MBC > 90 of 100 µM). All peptides showed minimal cytotoxicity against a cultured human cell line and non-toxic ADMET parameters in silico. This reductionist validation of a stability-pre-filtered computational shortlist substantiated VCP-VT1 as a priority bactericidal lead AMP. Its favourable preliminary efficacy and safety margins would warrant further pharmacokinetic optimization and eventual in vivo efficacy studies against recalcitrant multidrug-resistant (MDR) pathogens. This integrated computational-experimental framework provided a generally applicable strategy for accelerating the discovery of peptide-based therapeutics to combat the growing threat of AMR.

H. S. Mahrosh, M. Christodoulides, A. Jamil · Probiotics and Antimicrobial... · 0 citations

Open access Jul 2026

In silico discovery and interaction analysis of a Datura stramonium defensin-like peptide targeting cancer-related receptors.

Cancer continues to be a major global health burden, with receptor tyrosine kinases such as EGFR, ERBB2, and VEGFR-3 being critical therapeutic targets due to their central roles in tumor growth, survival, and angiogenesis. Current therapies, while effective in some contexts, face limitations including resistance, toxicity, and high cost, highlighting the need for novel multi-target approaches. In this study, we report the isolation and computational characterization of a novel defensin-like peptide (DEFL) from Datura stramonium (GenBank accession KT371458). The peptide sequence encoded 74 amino acids and displayed characteristic cysteine-stabilized motifs. Docking simulations revealed favorable binding scores toward EGFR (- 80.6 ± 10.6), ERBB2 (- 63.6 ± 7.4), and VEGFR-3 (- 50.5 ± 6.7), with interactions involving residues located within predicted receptor-binding regions. To further assess stability, 100 ns molecular dynamics simulations were performed. RMSD profiles confirmed stable complexes, with EGFR stabilizing around 0.6-0.8 nm, ERBB2 around 0.7-0.9 nm, and VEGFR-3 at a tighter 0.3-0.4 nm. Ligand RMSDs indicated moderate flexibility for ERBB2 (peaks up to 1.3 nm) but tighter stability for VEGFR-3 (0.3-0.5 nm). RMSF analyses revealed minimal fluctuations (< 0.3 nm) at binding sites, and radius of gyration values remained stable, indicating compact receptor-peptide complexes (EGFR: 3.45-3.75 nm; ERBB2: 2.95-3.20 nm; VEGFR-3: 1.92-1.98 nm). Hydrogen bond profiling and additional trajectory analyses (DCCM and PCA) supported overall system equilibration without major structural disruption during the simulations. The Datura stramonium defensin-like peptide indicating a stable and energetically favorable peptide-receptor interactions at the computational level. Overall, the simulations indicate persistent peptide-receptor association and stable structural behavior of the complexes at the computational level. However, molecular docking and molecular dynamics simulations do not demonstrate functional inhibition of EGFR, ERBB2, or VEGFR-3, nor do they confirm anticancer efficacy. Therefore, these results should be interpreted strictly as hypothesis-generating in silico predictions, and experimental validation, including peptide synthesis, receptor-binding assays, extracellular-domain competition assays, and cancer cell-based functional studies, will be required to confirm biological relevance.

Shehla Javaid, Zahid Mushtaq, A. Jamil et al. · Scientific Reports · 0 citations