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Pharmacophore modeling, multiple docking, and molecular dynamics studies on Wee1 kinase inhibitors.
J Biomol Struct Dyn. 2019 Jul; 37(10):2703-2715.JB

Abstract

Wee1-like protein kinase (Wee1) is a tyrosine kinase that regulates the G2 checkpoint and prevents entry into mitosis in response to DNA damage. Based on a series of signaling pathways initiated by Wee1, Wee1 has been recognized as a potential target for cancer therapy. To discover potent Wee1 inhibitors with novel scaffolds, ligand-based pharmacophore model has been built based on 101 known Wee1 inhibitors. Then the best pharmacophore model, AADRRR.340, with good partial least square (PLS) statistics (R2 = 0.9212, Q2 = 0.7457), was selected and validated. The validated model was used as a three-dimensional (3D) search query for databases virtual screening. The filtered molecules were further analyzed and refined by Lipinski's rule of 5, multiple docking procedures (high throughput virtual screening (HTVS), standard precision (SP), genetic optimization for ligand docking (GOLD), extra precision (XP), and unique quantum polarized ligand docking (QPLD)); absorption, distribution, metabolism, excretion, and toxicity (ADMET) screening; and the Prime/molecular mechanics generalized born surface area (MM-GBSA) method binding free energy calculations. Eight leads were identified as potential Wee1 inhibitors, and a 50 ns molecular dynamics (MD) simulation was carried out for top four inhibitors to predict the stability of ligand-protein complex. Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) based on MD simulation and the energy contribution per residue to the binding energy were calculated. In the end, three hits with good stabilization and affinity to protein were identified. Communicated by Ramaswamy H. Sarma.

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Publisher Full Text (DOI)

Authors+Show Affiliations

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

MeSH

AlgorithmsBinding SitesCell Cycle ProteinsDrug DiscoveryHumansHydrogen BondingLigandsMolecular Docking SimulationMolecular Dynamics SimulationMolecular StructureProtein BindingProtein Kinase InhibitorsProtein-Tyrosine KinasesQuantitative Structure-Activity RelationshipReproducibility of Results

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30052133

Citation

Hu, Yanqiu, et al. "Pharmacophore Modeling, Multiple Docking, and Molecular Dynamics Studies On Wee1 Kinase Inhibitors." Journal of Biomolecular Structure & Dynamics, vol. 37, no. 10, 2019, pp. 2703-2715.
Hu Y, Zhou L, Zhu X, et al. Pharmacophore modeling, multiple docking, and molecular dynamics studies on Wee1 kinase inhibitors. J Biomol Struct Dyn. 2019;37(10):2703-2715.
Hu, Y., Zhou, L., Zhu, X., Dai, D., Bao, Y., & Qiu, Y. (2019). Pharmacophore modeling, multiple docking, and molecular dynamics studies on Wee1 kinase inhibitors. Journal of Biomolecular Structure & Dynamics, 37(10), 2703-2715. https://doi.org/10.1080/07391102.2018.1495576
Hu Y, et al. Pharmacophore Modeling, Multiple Docking, and Molecular Dynamics Studies On Wee1 Kinase Inhibitors. J Biomol Struct Dyn. 2019;37(10):2703-2715. PubMed PMID: 30052133.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacophore modeling, multiple docking, and molecular dynamics studies on Wee1 kinase inhibitors. AU - Hu,Yanqiu, AU - Zhou,Lu, AU - Zhu,Xiaohong, AU - Dai,Duoqian, AU - Bao,Yinfeng, AU - Qiu,Yaping, Y1 - 2018/12/24/ PY - 2018/7/28/pubmed PY - 2020/6/25/medline PY - 2018/7/28/entrez KW - Wee1 inhibitors KW - binding free energy calculations KW - dynamics KW - pharmacophore model KW - quantum polarized ligand docking SP - 2703 EP - 2715 JF - Journal of biomolecular structure & dynamics JO - J Biomol Struct Dyn VL - 37 IS - 10 N2 - Wee1-like protein kinase (Wee1) is a tyrosine kinase that regulates the G2 checkpoint and prevents entry into mitosis in response to DNA damage. Based on a series of signaling pathways initiated by Wee1, Wee1 has been recognized as a potential target for cancer therapy. To discover potent Wee1 inhibitors with novel scaffolds, ligand-based pharmacophore model has been built based on 101 known Wee1 inhibitors. Then the best pharmacophore model, AADRRR.340, with good partial least square (PLS) statistics (R2 = 0.9212, Q2 = 0.7457), was selected and validated. The validated model was used as a three-dimensional (3D) search query for databases virtual screening. The filtered molecules were further analyzed and refined by Lipinski's rule of 5, multiple docking procedures (high throughput virtual screening (HTVS), standard precision (SP), genetic optimization for ligand docking (GOLD), extra precision (XP), and unique quantum polarized ligand docking (QPLD)); absorption, distribution, metabolism, excretion, and toxicity (ADMET) screening; and the Prime/molecular mechanics generalized born surface area (MM-GBSA) method binding free energy calculations. Eight leads were identified as potential Wee1 inhibitors, and a 50 ns molecular dynamics (MD) simulation was carried out for top four inhibitors to predict the stability of ligand-protein complex. Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) based on MD simulation and the energy contribution per residue to the binding energy were calculated. In the end, three hits with good stabilization and affinity to protein were identified. Communicated by Ramaswamy H. Sarma. SN - 1538-0254 UR - https://www.unboundmedicine.com/medline/citation/30052133/Pharmacophore_modeling_multiple_docking_and_molecular_dynamics_studies_on_Wee1_kinase_inhibitors_ DB - PRIME DP - Unbound Medicine ER -