Olatomide A. Fadare^1,, Temitayo O. Aiyelabola¹, Imisioluwa A. Akintola², Janet I. Michael¹, Rachael Y. Fadare¹, Chiamaka V. Chukwu¹, Folakemi O. Yakubu¹, Deborah A. Sanni¹, Roheemah O. Lawal¹, Akitsu Takashiro^3,, Adenike Kuku²

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–FLK14), designed by harvesting positively charged clusters from defensins identified in Nigerian edible plants and their corresponding Cu²⁺ complexes against two essential microbial enzymes: Candida albicans exo-β-(1,3)-glucanase (antifungal target) and Escherichia coli 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–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 3–4 to 5–6) and electrostatic contacts (from 1–2 to 3–4), consistent with metal-induced preorganization of peptide surface chemistry. In contrast, the rigid, quasi-spherical Cu²⁺–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–Cu²⁺ (pawpaw defensin) and FLK12–Cu²⁺ (tomato defensin) for antifungal development, and uncomplexed FLK1 (avocado), FLK5 (pawpaw), FLK11 (pawpaw), FLK13 (tomato), and FLK14 (tomato) for antibacterial applications. Collectively, these findings establish a structure–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.

peptides, exo-β-(1, 3)-glucanase, penicillin-binding protein 1B, antimicrobial resistance, molecular docking, metallopeptides