@article{ajps20261412,
author={{Fadare, Olatomide A. and Aiyelabola, Temitayo O. and Akintola, Imisioluwa A. and Michael, Janet I. and Fadare, Rachael Y. and Chukwu, Chiamaka V. and Yakubu, Folakemi O. and Sanni, Deborah A. and Lawal, Roheemah O. and Takashiro, Akitsu and Kuku, Adenike},
title={Docking-Based Evaluation of Defensin-Derived Peptides and Their Cu2? Complexes as Dual-Target Inhibitors of Exo-汕-(1,3)-Glucanase and Penicillin-Binding Protein Transglycosidase 1B},
journal={American Journal of Pharmacological Sciences},
volume={14},
number={1},
pages={7--19},
year={2026},
url={https://pubs.sciepub.com/ajps/14/1/2},
issn={2327-672X},
abstract={The escalating crisis of antimicrobial resistance necessitates the discovery of novel therapeutic agents with distinct mechanisms of action. Herein, we report a molecular docking study evaluating fourteen short amphiphilic peptides (FLK1每FLK14), designed by harvesting positively charged clusters from defensins identified in Nigerian edible plants and their corresponding Cu2? complexes against two essential microbial enzymes: <i>Candida albicans</i> exo-汕-(1,3)-glucanase (antifungal target) and <i>Escherichia coli</i> penicillin-binding protein 1B transglycosylase (antibacterial target). All uncomplexed peptides exhibited superior binding affinities relative to the native glucanase inhibitor (NFG, ?5.4 kcal/mol), with values ranging from ?6.0 to ?7.7 kcal/mol against glucanase and ?5.5 to ?7.0 kcal/mol against PBP1B. Cu2? complexation produced diametrically opposed effects on the two targets: dramatic enhancement of glucanase binding (with affinities reaching ?14.81 kcal/mol for FLK11每Cu2? derived from pawpaw defensin) versus near-universal loss of binding to PBP1B. Interaction fingerprint analysis revealed that Cu2? complexation promotes an ※interaction saturation§ state within the glucanase catalytic pocket, increasing hydrogen bonding (from 3每4 to 5每6) and electrostatic contacts (from 1每2 to 3每4), consistent with metal-induced preorganization of peptide surface chemistry. In contrast, the rigid, quasi-spherical Cu2?每peptide assemblies were sterically incompatible with the narrow hydrophobic groove of PBP1B, leading to impaired active-site penetration despite preserved surface charge. Lead candidates identified for experimental validation include FLK11每Cu2? (<i>pawpaw defensin</i>) and FLK12每Cu2? (<i>tomato defensin</i>) for antifungal development, and uncomplexed FLK1 (<i>avocado</i>), FLK5 (<i>pawpaw</i>), FLK11 (<i>pawpaw</i>), FLK13 (<i>tomato</i>), and FLK14 (<i>tomato</i>) for antibacterial applications. Collectively, these findings establish a structure每activity framework for the rational design of pathogen-selective metallopeptide inhibitors derived from locally available plant sources and demonstrate that metal coordination can function as a switchable modality to tune target selectivity rather than a universally beneficial modification.},
doi={10.12691/ajps-14-1-2}
publisher={Science and Education Publishing}
}