Shikimate Kinase 1 from Klebsiella pneumoniae as a New Drug Target Enzyme: Insights from Comparative Modeling and Molecular Dynamics
Yanping Li1,2, Suresh Kumar3★, Lihu Zhang1★★ Corresponding author
- 1Department of Pharmacy, Jiangsu Vocational College of Medicine, Yancheng, Jiangsu Province, CHINA.
- 2Post Graduate Centre, Management and Science University, University Drive, Off Persiaran Olahraga, Selangor, MALAYSIA.
- 3Department of Diagnostic and Allied Health Science, Faculty of Health and Life Sciences, Management and Science University, Shah Alam, MALAYSIA.
CORRESPONDENCE
Suresh Kumar
Dr. Lihu Zhang Department of Pharmacy, Jiangsu Vocational College of Medicine, 224005 Yancheng, Jiangsu Province, CHINA. Dr. Suresh Kumar Department of Diagnostic and Allied Health Science, Faculty of Health and Life Sciences, Management and Science University, Shah Alam, MALAYSIA. Email: sureshkumar@msu.edu.my
Received: 09-12-2023; Revised: 05-01-2024; Accepted: 06-07-2024.
Volume 58, Issue 4 · pp. 1110–1120 · PUBLISHED Jul-Sep 2024 · DOI: 10.5530/ijper.58.4.122
ABSTRACT
Background Klebsiella pneumoniae, a Gram-negative bacterium, is an established nosocomial pathogen that is particularly dangerous to immunosuppressed individuals, causing diseases such as sepsis, pneumonia, urinary tract infections and respiratory tract infections. The emergence of multidrug resistant strains of this bacterium poses a significant challenge to current therapeutic strategies, highlighting the urgent need for new drug targets. Materials and Methods Our study highlights the shikimate pathway as a source of such targets, given its role in the production of essential aromatic compounds in various organisms, but its absence in humans. We focus on Shikimate Kinase 1 (SK-1), encoded by the aroK gene in K. pneumoniae and use it as a model for inhibitor development. Through comparative modelling, structural validation is using Ramachandran plots, ERRAT and Verify3D and stability checks using energy minimization and molecular dynamics simulations. Results In the Ramachandran plot validation, AlphaFold2 performed better than the other three predicted models (SWISS-MODEL, Phyre2 servers, I-TASSER). The Ramachandran plot analysis showed 90.8% residues in the preferred region, 8.8% residues in the allowed region. When Desmond’s energy minimization calculations were applied to the models, AlphaFold2 showed the lowest energy. In addition, MD simulations representing a stable conformation were applied to the reduced structure. Conclusion This provides a basis for molecular coupling and the exploration of new inhibitors, offering promising avenues for the development of treatments against K. pneumoniae.
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Li, Y., Kumar, S., & Zhang, L. (2024). Shikimate Kinase 1 from Klebsiella pneumoniae as a New Drug Target Enzyme: Insights from Comparative Modeling and Molecular Dynamics. Indian Journal of Pharmaceutical Education and Research, 58(4), 1110–1120. https://doi.org/10.5530/ijper.58.4.122