COMPUTATIONAL SCREENING OF ALKALOIDS TO ELIMINATE PSEUDOMONAS AERUGINOSA BASED ON THE INHIBITION OF PROTEINS INVOLVED IN PEPTIDOGLYCAN BIOSYNTHESIS

Nguyễn Tấn Khanh; Phạm Thị Khánh Huyền; Trần Mạnh Hùng; Trần Ngọc Anh Thư; Võ Đức Huy; Phạm Trần Vĩnh Phú

doi:10.34238/tnu-jst.12317

COMPUTATIONAL SCREENING OF ALKALOIDS TO ELIMINATE PSEUDOMONAS AERUGINOSA BASED ON THE INHIBITION OF PROTEINS INVOLVED IN PEPTIDOGLYCAN BIOSYNTHESIS

About this article

Received: 16/03/25 Revised: 10/08/25 Published: 11/08/25

Authors

1. Nguyen Tan Khanh, Dong A University
2. Pham Thi Khanh Huyen, College of Pharmacy - Dongguk University-Seoul, Republic of Korea
3. Tran Manh Hung, School of Medicine and Pharmacy - The University of Danang
4. Tran Ngoc Anh Thu, VN-UK Institute for Research and Executive Education - The University of Danang
5. Vo Duc Huy, VN-UK Institute for Research and Executive Education - The University of Danang
6. Pham Tran Vinh Phu , VN-UK Institute for Research and Executive Education - The University of Danang

Abstract

Pseudomonas aeruginosa is a Gram-negative pathogen responsible for severe nosocomial infections, demonstrating high adaptability and multidrug resistance. The increasing prevalence of multidrug resistant P. aeruginosa necessitates novel antimicrobial strategies, primarily targeting essential bacterial enzymes. This study aimed to identify potential alkaloid inhibitors targeting D-alanine:D-alanine ligase and Alanine racemase, key enzymes involved in bacterial cell wall synthesis. A machine learning-based regression model was developed using a ChEMBL database dataset to predict alkaloids' inhibitory activity against P. aeruginosa. Molecular docking simulations assessed the binding interactions between selected alkaloids and D-alanine:D-alanine ligase or Alanine racemase. The study identified 10-Hydroxycamptothecin as a potent inhibitor, exhibiting the highest docking affinity against D-alanine:D-alanine ligase (-8.01 kcal/mol) and alanine racemase (-8.928 kcal/mol) and favorable interactions with key residues. Absorption, distribution, metabolism, excretion, and toxicity analysis revealed high gastrointestinal absorption for all selected compounds, with some exhibiting blood-brain barrier permeability. Toxicity predictions indicated a low risk of hepatotoxicity and cardiotoxicity but raised concerns regarding potential neurotoxicity and nephrotoxicity. These findings suggest that alkaloids, particularly camptothecin derivatives, hold promise as scaffolds for novel antibiotics targeting P. aeruginosa. Further wet experimental validation is required to confirm the efficacy and safety selected alkaloids.

Keywords

Alkaloids; Alanine racemase; Antibiotics; D-alanine:D-alanine ligase; Pseudomonas aeruginosa

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DOI: https://doi.org/10.34238/tnu-jst.12317

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