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Discovery of promising FtsZ inhibitors by E-pharmacophore, 3D-QSAR, molecular docking study, and molecular dynamics simulation.
J Recept Signal Transduct Res. 2019 Apr; 39(2):154-166.JR

Abstract

Asbtract Filamentous temperature-sensitive protein Z (FtsZ), playing a key role in bacterial cell division, is regarded as a promising target for the design of antimicrobial agent. This study is looking for potential high-efficiency FtsZ inhibitors. Ligand-based pharmacophore and E-pharmacophore, virtual screening and molecular docking were used to detect promising FtsZ inhibitors, and molecular dynamics simulation was used to study the stability of protein-ligand complexes in this paper. Sixty-three inhibitors from published literatures with pIC50 ranging from 2.483 to 5.678 were collected to develop ligand-based pharmacophore model. 4DXD bound with 9PC was selected to develop the E-pharmacophore model. The pharmacophore models validated by test set method and decoy set were employed for virtual screening to exclude inactive compounds against ZINC database. After molecular docking, ADME analysis, IFD docking and MM-GBSA, 8 hits were identified as potent FtsZ inhibitors. A 50 ns molecular dynamics simulation was implemented on the compounds to assess the stability between potent inhibitors and FtsZ. The results indicated that the candidate compounds had a high docking score and were strongly combined with FtsZ by forming hydrogen bonding interactions with key amino acid residues, and van der Waals forces and hydrophobic interactions had significant contribution to the stability of the binding. Molecular dynamics simulation results showed that the protein-ligand compounds performed well in both the stability and flexibility of the simulation process.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Qiu Y
a College of Chemical Engineering, Sichuan University , Chengdu , China.
Zhou L
a College of Chemical Engineering, Sichuan University , Chengdu , China.
Hu Y
a College of Chemical Engineering, Sichuan University , Chengdu , China.
Bao Y
a College of Chemical Engineering, Sichuan University , Chengdu , China.

MeSH

Anti-Infective AgentsBacterial ProteinsBinding SitesCell DivisionCrystallography, X-RayCytoskeletal ProteinsHumansHydrogen BondingHydrophobic and Hydrophilic InteractionsLigandsMolecular Docking SimulationMolecular Dynamics SimulationProtein ConformationQuantitative Structure-Activity RelationshipTemperature

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31355691

Citation

Qiu, Yaping, et al. "Discovery of Promising FtsZ Inhibitors By E-pharmacophore, 3D-QSAR, Molecular Docking Study, and Molecular Dynamics Simulation." Journal of Receptor and Signal Transduction Research, vol. 39, no. 2, 2019, pp. 154-166.
Qiu Y, Zhou L, Hu Y, et al. Discovery of promising FtsZ inhibitors by E-pharmacophore, 3D-QSAR, molecular docking study, and molecular dynamics simulation. J Recept Signal Transduct Res. 2019;39(2):154-166.
Qiu, Y., Zhou, L., Hu, Y., & Bao, Y. (2019). Discovery of promising FtsZ inhibitors by E-pharmacophore, 3D-QSAR, molecular docking study, and molecular dynamics simulation. Journal of Receptor and Signal Transduction Research, 39(2), 154-166. https://doi.org/10.1080/10799893.2019.1638404
Qiu Y, et al. Discovery of Promising FtsZ Inhibitors By E-pharmacophore, 3D-QSAR, Molecular Docking Study, and Molecular Dynamics Simulation. J Recept Signal Transduct Res. 2019;39(2):154-166. PubMed PMID: 31355691.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery of promising FtsZ inhibitors by E-pharmacophore, 3D-QSAR, molecular docking study, and molecular dynamics simulation. AU - Qiu,Yaping, AU - Zhou,Lu, AU - Hu,Yanqiu, AU - Bao,Yinfeng, Y1 - 2019/07/29/ PY - 2019/7/30/pubmed PY - 2020/1/14/medline PY - 2019/7/30/entrez KW - FtsZ KW - induced fit docking KW - molecular dynamics simulation KW - pharmacophore SP - 154 EP - 166 JF - Journal of receptor and signal transduction research JO - J Recept Signal Transduct Res VL - 39 IS - 2 N2 - Asbtract Filamentous temperature-sensitive protein Z (FtsZ), playing a key role in bacterial cell division, is regarded as a promising target for the design of antimicrobial agent. This study is looking for potential high-efficiency FtsZ inhibitors. Ligand-based pharmacophore and E-pharmacophore, virtual screening and molecular docking were used to detect promising FtsZ inhibitors, and molecular dynamics simulation was used to study the stability of protein-ligand complexes in this paper. Sixty-three inhibitors from published literatures with pIC50 ranging from 2.483 to 5.678 were collected to develop ligand-based pharmacophore model. 4DXD bound with 9PC was selected to develop the E-pharmacophore model. The pharmacophore models validated by test set method and decoy set were employed for virtual screening to exclude inactive compounds against ZINC database. After molecular docking, ADME analysis, IFD docking and MM-GBSA, 8 hits were identified as potent FtsZ inhibitors. A 50 ns molecular dynamics simulation was implemented on the compounds to assess the stability between potent inhibitors and FtsZ. The results indicated that the candidate compounds had a high docking score and were strongly combined with FtsZ by forming hydrogen bonding interactions with key amino acid residues, and van der Waals forces and hydrophobic interactions had significant contribution to the stability of the binding. Molecular dynamics simulation results showed that the protein-ligand compounds performed well in both the stability and flexibility of the simulation process. SN - 1532-4281 UR - https://www.unboundmedicine.com/medline/citation/31355691/Discovery_of_promising_FtsZ_inhibitors_by_E_pharmacophore_3D_QSAR_molecular_docking_study_and_molecular_dynamics_simulation_ DB - PRIME DP - Unbound Medicine ER -

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