In silico discovery of druggable targets in Citrobacter koseri using echinoderm metabolites and molecular dynamics simulation

Abstract

Citrobacter koseri causes infection in people who are immunocompromised. Without effective antibiotics, these infections can become severe and life-threatening, so effective drugs are essential to treat these infections. Utilizing subtractive genomics, 2699 ORFs were predicted and translated into amino acid sequences. Metabolic pathway analysis and subcellular localization helped define the roles of key bacterial proteins. Two druggable proteins, WP_012000829.1 and WP_275157394.1, were discovered as promising targets. Alpha Fold provided 3D structures, and a library of 1600 echinoderm metabolites was docked against these proteins, with Ampicillin, Levofloxacin, and Doxycycline as controls. Notably, CMNPD13085 and CMNPD15632 exhibited the highest binding affinities for WP_012000829.1 and WP_275157394.1, respectively. Molecular dynamics simulations and MM-GBSA binding free energy complemented docking results. However, acknowledging the reliance on computational validations, the study emphasizes the need for essential in-vitro research to transform these potential inhibitors into therapeutic drugs.

Keywords: Citrobacter koseri; Immunocompromised; MD simulation; MMGBSA; Molecular docking; Subtractive genomics.

Fig. 1

The plausible binding modes and molecular interactions of the selected compounds with the proteins. (a) The binding mode of CMNPD13085 against WP_012000829.1 (b) The molecular interactions of CMNPD13085 with protein. (c) The binding mode of CMNPD15632 against WP_275157394.1 (d) The molecular interactions of CMNPD15632 with protein. The molecular interactions are represented with the green (hydrogen bonds) and Magenta (Hydrophobic) spheres.

Fig. 2

The MD trajectory analysis to calculate the RMSD of carbon alpha atoms of protein complexes. (a) WP_012000829.1 complexed with control, (b) WP_012000829.1 complexed with CMNPD13085. (c) WP_275157394.1 complexed with control (d) WP_275157394.1 complexed with CMNPD15632.

Fig. 3

The MD trajectory analysis to calculate the RMSF of carbon alpha atoms of protein complexes. (a) WP_012000829.1 complexed with control, (b) WP_012000829.1 complexed with CMNPD13085. (c) WP_275157394.1 complexed with control (d) WP_275157394.1 complexed with CMNPD15632.

Fig. 4

Protein-ligand contacts calculated during simulation. (a) WP_012000829.1 complexed with control, (b) WP_012000829.1 complexed with CMNPD13085. (c) WP_275157394.1 complexed with control (d) WP_275157394.1 complexed with CMNPD15632.