Targeting Shikimate Kinase Pathway of Acinetobacter baumannii: A Structure-Based Computational Approach to Identify Antibacterial Compounds

Abstract

Acinetobacter baumannii (A. baumannii) is an opportunistic bacterium that has developed multidrug resistance (MDR) to most of today's antibiotics, posing a significant risk to human health. Considering the fact that developing novel drugs is a time-consuming and expensive procedure, this research focuses on utilizing computational resources for repurposing antibacterial agents for A. baumannii. We targeted shikimate kinase, an essential enzyme in A. baumannii, that plays a significant role in the metabolic process. The basis for generating new therapeutic compounds is to inhibit the shikimate kinase and thereby targeting the shikimate pathway. Herein, 1941 drug-like compounds were investigated in different in silico techniques for assessing drug-likeness properties, ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling, binding affinity, and conformation analysis utilizing Autodock-vina and SwissDock. CHEMBL1237, CHEMBL1237119, CHEMBL2018096, and CHEMBL39167178 were determined as potential drug candidates for suppressing shikimate kinase protein. Molecular Dynamics Simulation (MDS) results for root mean square deviation, root mean square fluctuation, hydrogen bond, and gyration radius confirm the drug candidates' molecular stability with the target protein. According to this study, CHEMBL1237 (Lisinopril) could be the most suitable candidate for A. baumannii. Our investigation suggests that the inhibitors of shikimate kinase could represent promising treatment options for A. baumannii. However, further in vitro and in vivo studies are necessary to validate the therapeutic potential of the suggested drug candidates.

Figure 1

Schematic representation of Shikimate kinase_CHEMBL1237 complex. (a) Pose view of Shikimate kinase_CHEMBL123 complex. (b) Surface view of Shikimate kinase_CHEMBL123 complex. Here, protein is in red, yellow, and green color and ligand is in blue color. (c, d) 3D and 2D interaction of Shikimate kinase_CHEMBL123 complex. Here, protein is in green color and ligand is in blue color.

Figure 2

Schematic representation of Shikimate kinase_CHEMBL1237119 complex. (a) Pose view of Shikimate kinase_CHEMBL1237119 complex. (b) Surface view of Shikimate kinase_CHEMBL1237119 complex. Here, protein is in red, yellow, and green color and ligand is in blue color. (c, d) 3D and 2D interaction of Shikimate kinase_CHEMBL1237119 complex. Here, protein is in green color and ligand is in blue color.

Figure 3

Schematic representation of Shikimate kinase_CHEMBL2018096 complex. (a) Pose view of Shikimate kinase_CHEMBL2018096 complex. (b) Surface view of Shikimate kinase_CHEMBL2018096 complex. Here, protein is in red, yellow, and green color and ligand is in blue color. (c, d) 3D and 2D interaction of Shikimate kinase_CHEMBL2018096 complex. Here, protein is in green color and ligand is in blue color.

Figure 4

Schematic representation of Shikimate kinase_CHEMBL3916717 complex. (a) Pose view of Shikimate kinase_CHEMBL3916717 complex. (b) Surface view of Shikimate kinase_CHEMBL3916717 complex. Here, protein is in red, yellow, and green color and ligand is in blue color. (c, d) 3D and 2D interaction of Shikimate kinase_CHEMBL3916717 complex. Here, protein is in green color and ligand is in blue color.

Figure 5

Schematic presentation of simulation plots. The plots represent features of (a) root mean square deviation (RMSD), (b) root mean square fluctuation (RMSF), (c) radius of gyration (Rg), (d) solvent-accessible surface area (SASA), and (e) hydrogen bonds (H-bonds) at 100 nanoseconds of molecular dynamics simulation using the GROMACS software.

Figure 6

Graphical presentation of simulation curves. The plots represent features of (a, b) root mean square deviation (RMSD) and (c) root mean square fluctuation (RMSF), at 100 nanoseconds of molecular dynamics simulation using Desmond software.

Figure 7

Diagram of protein-ligand complex chart of (a) Shikimate kinase_CHEMBL1237, (b) Shikimate kinase_CHEMBL1237119, (c) Shikimate kinase_CHEMBL2018096, (d) Shikimate kinase_CHEMBL3916717, and (e) Shikimate kinase_Doxycycline complexes.