Structure based drug design of Pim-1 kinase followed by pharmacophore guided synthesis of quinolone-based inhibitors
| Autor: | Alaa Hasan, Rand Shahin, Lubna Swellmeen, O. H. Shaheen, Yusuf Al-Hiari, Amani Alamiri |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
medicine.drug_class
Stereochemistry Clinical Biochemistry Protein Data Bank (RCSB PDB) Pharmaceutical Science Quinolones 010402 general chemistry 01 natural sciences Biochemistry Proto-Oncogene Proteins c-pim-1 Drug Discovery medicine Humans Molecular Biology IC50 Protein Kinase Inhibitors Binding Sites 010405 organic chemistry Chemistry Kinase Organic Chemistry computer.file_format Protein Data Bank Quinolone 0104 chemical sciences Protein Structure Tertiary Molecular Docking Simulation ROC Curve Area Under Curve Drug Design Molecular Medicine Kinase binding Pharmacophore computer Databases Chemical Discovery Studio Protein Binding |
| Zdroj: | Bioorganicmedicinal chemistry. 25(17) |
| ISSN: | 1464-3391 |
| Popis: | Over expression of Human phosphatidyl inositol mannoside kinases isoform 1 (Pim-1 kinase) has been reported in several leukemia and solid tumors. Our continuous interest to reveal the secrecies of the mysterious Pim-1 kinase binding pocket has led us to employ a structure based drug design procedure based on receptor-ligand pharmacophore generation protocol implemented in Discovery Studio 4.5 (DS 4.5). Subsequently, we collected 104 crystal structures of Pim-1 kinase from the Protein Data Bank (PDB) and used them to generate pharmacophores based on the anticipated co-crystallized ligand-Pim 1 kinase receptor interactions. All selected pharmacophoric features were enumerated and only those that had corresponding valuable receptor-ligand interactions were retained. This was followed by modeling all pharmacophore combinations and scoring them according to their Receiver Operating Characteristic (ROC) curve analysis parameters as well as a DS.4.5 built-in Genetic Function Algorithm (GFA) validating model. Accordingly, 111 pharmacophores resulted with acceptable ROC performances; 1XWS_2_04, 2BIK_2_06, and 1XWS_2_06 (ROC AUC value of: 0.770, 0.743 and 0.741 respectively) were the best pharmacophores. These pharmacophores were employed to guide the synthesis of new series of 7-[(2-Carboxyethyl)amino]-1-substituted-6-fluoro-8-nitro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and their reduced 8-amino derivatives. The synthesized compounds were later evaluated for their Pim-1 kinase inhibitory potencies. Of which the most potent illustrated an IC50 value of 0.29µM against Pim-1 kinase. |
| Databáze: | OpenAIRE |
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