Docking-Based Evaluation of Defensin-Derived Peptides and Their Cu²⁺ Complexes as Dual-Target Inhibitors of Exo-β-(1,3)-Glucanase and Penicillin-Binding Protein Transglycosidase 1B

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, and Adenike Kuku²

¹Department of Chemistry, Obafemi Awolowo University, Ile-Ife, Nigeria

²Department of Chemical Sciences, Kings University, Ode Omu, Osun State, Nigeria

³Department of Chemistry, Faculty of Science, Tokyo University of Science, Japan

Cite this paper:
Olatomide A. Fadare, Temitayo O. Aiyelabola, Imisioluwa A. Akintola, Janet I. Michael, Rachael Y. Fadare, Chiamaka V. Chukwu, Folakemi O. Yakubu, Deborah A. Sanni, Roheemah O. Lawal, Akitsu Takashiro and Adenike Kuku. Docking-Based Evaluation of Defensin-Derived Peptides and Their Cu²⁺ Complexes as Dual-Target Inhibitors of Exo-β-(1,3)-Glucanase and Penicillin-Binding Protein Transglycosidase 1B. American Journal of Pharmacological Sciences. 2026; 14(1):7-19. doi: 10.12691/ajps-14-1-2

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–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.

Keywords:
peptides exo-β-(13)-glucanase penicillin-binding protein 1B antimicrobial resistance molecular docking metallopeptides

This work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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