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Virtual screening to identify novel potential inhibitors for Glutamine synthetase of Mycobacterium tuberculosis.
J Biomol Struct Dyn. 2019 Dec 06 [Online ahead of print]JB

Abstract

Glutamine synthetase (GS) of Mycobacterium tuberculosis (Mtb) is an essential enzyme which is involved in nitrogen metabolism and cell wall synthesis. It is involved in the inhibition of phagosome-lysosome fusion by preventing acidification. Targeting GS can be helpful to control the infection of Mtb. In order to identify potential inhibitors, we screened chemical libraries (56,400 compounds of ChEMBL anti-mycobacterial, 1596 FDA approved drugs, 419 Natural product and 916 phytochemical) against this target using the virtual screening approach. Screening by molecular docking identified ten top-ranked compounds as GSMtb inhibitors and they were compared with known inhibitors (as control). Since GS enzyme (GSHs) is also present in human. We have compared the protein sequence of GS from Mtb and human using the P-BLAST in NCBI. We found ∼27% identity in between these two sequences, so we also compared the binding affinity of inhibitor between Mtb and human. Finally, we identified top two compounds namely CHEMBL387509, CHEMBL226198 from ChEMBL anti-mycobacterial dataset, and Eriocitrin and Malvidin from phytochemical dataset which showed lees binding affinity towards GSHs whereas Pamidronate, and Phentermine from FDA approved drugs and (-)-Quinic Acid, Hexopyranuronic acid, Quebrachit, and Castanospermine from natural product showed protein-ligand interaction with Mtb protein while no interaction with GSHs. The top two docked complexes were subjected to molecular dynamic simulation to understand the stability of the molecule. Further, we calculated the binding free energy of the docked complex and analyzed hydrogen bond, salt bridge, pie stacking, and hydrophobic interaction in the docking region. These ligands exhibited very good binding affinity GSMtb enzymes. Therefore, these ligands are novel and drug-likeness compounds, and they may be potential inhibitors of M tuberculosis.Communicated by Ramaswamy H. Sarma.

Authors+Show Affiliations

School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India.School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31755360

Citation

Kumari, Madhulata, and Naidu Subbarao. "Virtual Screening to Identify Novel Potential Inhibitors for Glutamine Synthetase of Mycobacterium Tuberculosis." Journal of Biomolecular Structure & Dynamics, 2019, pp. 1-19.
Kumari M, Subbarao N. Virtual screening to identify novel potential inhibitors for Glutamine synthetase of Mycobacterium tuberculosis. J Biomol Struct Dyn. 2019.
Kumari, M., & Subbarao, N. (2019). Virtual screening to identify novel potential inhibitors for Glutamine synthetase of Mycobacterium tuberculosis. Journal of Biomolecular Structure & Dynamics, 1-19. https://doi.org/10.1080/07391102.2019.1695670
Kumari M, Subbarao N. Virtual Screening to Identify Novel Potential Inhibitors for Glutamine Synthetase of Mycobacterium Tuberculosis. J Biomol Struct Dyn. 2019 Dec 6;1-19. PubMed PMID: 31755360.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Virtual screening to identify novel potential inhibitors for Glutamine synthetase of Mycobacterium tuberculosis. AU - Kumari,Madhulata, AU - Subbarao,Naidu, Y1 - 2019/12/06/ PY - 2019/11/23/pubmed PY - 2019/11/23/medline PY - 2019/11/23/entrez KW - Glutamine synthetase KW - MD simulation KW - Molecular docking KW - Mycobacterium tuberculosis KW - binding free energy KW - virtual screening SP - 1 EP - 19 JF - Journal of biomolecular structure & dynamics JO - J. Biomol. Struct. Dyn. N2 - Glutamine synthetase (GS) of Mycobacterium tuberculosis (Mtb) is an essential enzyme which is involved in nitrogen metabolism and cell wall synthesis. It is involved in the inhibition of phagosome-lysosome fusion by preventing acidification. Targeting GS can be helpful to control the infection of Mtb. In order to identify potential inhibitors, we screened chemical libraries (56,400 compounds of ChEMBL anti-mycobacterial, 1596 FDA approved drugs, 419 Natural product and 916 phytochemical) against this target using the virtual screening approach. Screening by molecular docking identified ten top-ranked compounds as GSMtb inhibitors and they were compared with known inhibitors (as control). Since GS enzyme (GSHs) is also present in human. We have compared the protein sequence of GS from Mtb and human using the P-BLAST in NCBI. We found ∼27% identity in between these two sequences, so we also compared the binding affinity of inhibitor between Mtb and human. Finally, we identified top two compounds namely CHEMBL387509, CHEMBL226198 from ChEMBL anti-mycobacterial dataset, and Eriocitrin and Malvidin from phytochemical dataset which showed lees binding affinity towards GSHs whereas Pamidronate, and Phentermine from FDA approved drugs and (-)-Quinic Acid, Hexopyranuronic acid, Quebrachit, and Castanospermine from natural product showed protein-ligand interaction with Mtb protein while no interaction with GSHs. The top two docked complexes were subjected to molecular dynamic simulation to understand the stability of the molecule. Further, we calculated the binding free energy of the docked complex and analyzed hydrogen bond, salt bridge, pie stacking, and hydrophobic interaction in the docking region. These ligands exhibited very good binding affinity GSMtb enzymes. Therefore, these ligands are novel and drug-likeness compounds, and they may be potential inhibitors of M tuberculosis.Communicated by Ramaswamy H. Sarma. SN - 1538-0254 UR - https://www.unboundmedicine.com/medline/citation/31755360/Virtual_screening_to_identify_novel_potential_inhibitors_for_Glutamine_synthetase_of_Mycobacterium_tuberculosis L2 - http://www.tandfonline.com/doi/full/10.1080/07391102.2019.1695670 DB - PRIME DP - Unbound Medicine ER -
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