Identification of p38α MAP kinase inhibitors by pharmacophore based virtual screening

• Published in: Journal of molecular graphics & modelling Vol. 49; pp. 18 - 24
• Main Authors: Gangwal, Rahul P., Das, Nihar R., Thanki, Kaushik, Damre, Mangesh V., Dhoke, Gaurao V., Sharma, Shyam S., Jain, Sanyog, Sangamwar, Abhay T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2014
• Subjects: Cytotoxicity; Hep G2 Cells; Humans; Molecular docking; p38 MAP kinase; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - chemistry; Pharmacophore modeling; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Structure-Activity Relationship; Tumor Necrosis Factor-alpha; Virtual screening; Virtual screening; p38 MAP kinase; Pharmacophore modeling; Cytotoxicity; Molecular docking
• ISSN: 1093-3263; 1873-4243
• DOI: 10.1016/j.jmgm.2014.01.002

•Bioactive confirmations were used to develop and validate pharmacophore hypotheses.•A combined pharmacophore model was designed to identify novel p38 MAP kinase inhibitors.•Identified hits were biologically evaluated for p38 MAP kinase and TNF-α inhibition.•Cytotoxicity in HepG2 cell line was determined for identified hits. 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 10μM concentration. Out of these seven compounds has shown potent inhibitory activity against p38 MAP kinase with IC50 values ranging from 12.97 to 223.5nM. In addition, the toxicity study against HepG2 cells was also carried out to confirm the safety profile of identified virtual hits.