Background Neisseria gonorrhoeae, a causative agent of gonorrhea, has developed resistance to most of the drugs and hence aptly declared as ‘Superbug’. Glutamate racemase (MurI) considered as an important drug target. Therefore, identification of novel drugs for the treatment of gonorrhea is urgently required.
Methods The amino acid sequence of MurI of Neisseria gonorrhoeae (YP_208550) was retrieved from NCBI. Based on query coverage, e-score and percentage similarity, 3OUT (glutamate racemase from Francisella tularensis) was selected as template after PDB BLAST, homology model was generated by Modeller programme of Discovery Studio 4.0.Best model was selected based on DOPE score and PDF energy score and further verified by Verify-3D protocol and Ramachandran Plot. Receptor binding site was identified after superimposition of template structure and modelled structure and the co-crystalized ligand of the template was docked into the modeled MurI structure. Based on docking score, best pose was selected and receptor-ligand pharmacophore model was generated.
Results The best homology model generated was selected based on the verify score of 107.93 from Verify 3D program of Discovery Studio 4.0. Validation of the selected model by Ramachandran plot showed214 residues (91.8%) fall in most favored region. RMSD of 0.2475 A0was generated by superimposition of query and template structures. Quality factorof 84% for the protein models was obtained using ERRAT.Six pharmacophores were generated using best docking pose between D-glutamate and MurI. These were subjected to virtual screening with DrugBank database.586 hits so obtained were filtered by fit value of 3.51which resulted in268 hits.These 268 hits were further subjected to Lipinski and veber filter followed by ADMET, gave 73 hits. These were subjected to energy minimization and docking to obtain the best hits.
Conclusion The study identifies potential compounds that interact with active site of MurI protein, opening new avenues for the treatment option against multidrug resistant strains.
Disclosure No significant relationships.
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