Identification of p38α MAP kinase inhibitors by pharmacophore based virtual screening |
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| Affiliation: | 1. Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Punjab 160 062, India;2. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Punjab 160 062, India;3. Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar (Mohali), Phase X, Sector-67, Punjab 160 062, India;1. Department of Chemistry, Suleyman Demirel University, 32260 Isparta, Turkey;2. Department of Polymer Engineering, Karabuk University, 78050 Karabuk, Turkey;3. Instituto de Estructura de la Materia, IEM-CSIC, Serrano 123, 28006 Madrid, Spain;4. Unidad Asociada Química Física UCM/IEM-CSIC, Departamento de Química Física I, Universidad Complutense, 28040 Madrid, Spain;1. Laboratory of the Physico-Chemistry of Solid States, LR11 ES51 of Sfax, Road of Soukra km 4, Sfax 3071, Tunisia;2. Laboratoire de Chimie Appliquée: Hétérocycles, Corps gras et Polyme‘res, Facultédes Sciences de Sfax, BP 802, 3018 Sfax, Tunisia;1. Department of Applied Physics, Guru Jambheshwar University of Science & Technology, Hisar 125001, Haryana, India;2. National Physical Laboratory, Dr. K. S. Krishnan Marg, New Delhi 110012, India |
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| Abstract: | The p38α mitogen-activated protein (MAP) kinase plays a vital role in treating many inflammatory diseases. In the present study, a combined ligand and structure based pharmacophore model was developed to identify potential DFG-in selective p38 MAP kinase inhibitors. Conformations of co-crystallised inhibitors were used in the development and validation of ligand and structure based pharmacophore modeling approached. The validated pharmacophore was utilized in database screening to identify potential hits. After Lipinski's rule of five filter and molecular docking analysis, nineteen hits were purchased and selected for in vitro analysis. The virtual hits exhibited promising activity against tumor necrosis factor-α (TNF-α) with 23–98% inhibition at 10 μM concentration. Out of these seven compounds has shown potent inhibitory activity against p38 MAP kinase with IC50 values ranging from 12.97 to 223.5 nM. In addition, the toxicity study against HepG2 cells was also carried out to confirm the safety profile of identified virtual hits. |
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| Keywords: | Cytotoxicity Molecular docking p38 MAP kinase Pharmacophore modeling Virtual screening |
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