Pharmacophore modeling, multiple docking, and molecular dynamics studies on Wee1 kinase inhibitors
| Autor: | Yanqiu Hu, Duoqian Dai, Yinfeng Bao, Xiaohong Zhu, Yaping Qiu, Lu Zhou |
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| Rok vydání: | 2018 |
| Předmět: |
030303 biophysics
Quantitative Structure-Activity Relationship Cell Cycle Proteins Molecular Dynamics Simulation Ligands 03 medical and health sciences Structural Biology Drug Discovery Humans Protein kinase A Molecular Biology Protein Kinase Inhibitors 0303 health sciences Binding Sites biology Molecular Structure Chemistry Kinase Reproducibility of Results Hydrogen Bonding General Medicine G2-M DNA damage checkpoint Protein-Tyrosine Kinases Cell biology Molecular Docking Simulation Wee1 Docking (molecular) biology.protein Pharmacophore Signal transduction Tyrosine kinase Algorithms Protein Binding |
| Zdroj: | Journal of biomolecular structuredynamics. 37(10) |
| ISSN: | 1538-0254 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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