Shikimate Kinase 1 from Klebsiella pneumoniae as a New Drug Target Enzyme: Insights from Comparative Modeling and Molecular Dynamics

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.

Keywords: Klebsiella pneumoniae; Shikimate Kinase 1; Comparative modeling; AlphaFold2; Molecular dynamics simulations