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Insights into the Interaction Mechanisms of the Proviral Integration Site of Moloney Murine Leukemia Virus (Pim) Kinases with Pan-Pim Inhibitors PIM447 and AZD1208: A Molecular Dynamics Simulation and MM/GBSA Calculation Study
- Source :
- International Journal of Molecular Sciences, Volume 20, Issue 21, International Journal of Molecular Sciences, Vol 20, Iss 21, p 5410 (2019)
- Publication Year :
- 2019
- Publisher :
- Multidisciplinary Digital Publishing Institute, 2019.
-
Abstract
- Based on the up-regulation of the proviral integration site of the Moloney murine leukemia virus (Pim) kinase family (Pim1, 2, and 3) observed in several types of leukemias and lymphomas, the development of pan-Pim inhibitors is an attractive therapeutic strategy. While only PIM447 and AZD1208 have entered the clinical stages. To elucidate the interaction mechanisms of three Pim kinases with PIM447 and AZD1208, six Pim/ligand systems were studied by homology modeling, molecular docking, molecular dynamics (MD) simulation and molecular mechanics/generalized Born surface area (MM/GBSA) binding free energy calculation. The residues of the top group (Leu44, Val52, Ala65, Lys67, and Leu120 in Pim1) dominated the pan-Pim inhibitors binding to Pim kinases. The residues of the bottom group (Gln127, Asp128, and Leu174 in Pim1) were crucial for Pims/PIM447 systems, while the contributions of these residues were decreased sharply for Pims/AZD1208 systems. It is likely that the more potent pan-Pim inhibitors should be bound strongly to the top and bottom groups. The residues of the left, right and loop groups were located in the loop regions of the binding pocket, however, the flexibility of these regions triggered the protein interacting with diverse pan-Pim inhibitors efficiently. We hope this work can provide valuable information for the design of novel pan-Pim inhibitors in the future.
- Subjects :
- Models, Molecular
0301 basic medicine
Protein Conformation
01 natural sciences
lcsh:Chemistry
Molecular dynamics
hemic and lymphatic diseases
Murine leukemia virus
MM/GBSA calculation
lcsh:QH301-705.5
Spectroscopy
Pim kinase
biology
Chemistry
General Medicine
Ligand (biochemistry)
Computer Science Applications
Molecular Docking Simulation
molecular dynamics simulation
Pim kinases
Thiazolidines
Protein Binding
Proviral integration
Virus Attachment
PIM1
Computational biology
Molecular mechanics
Article
Catalysis
PIM447
Inorganic Chemistry
Structure-Activity Relationship
03 medical and health sciences
Proto-Oncogene Proteins c-pim-1
Cell Line, Tumor
Humans
Homology modeling
Physical and Theoretical Chemistry
AZD1208
Protein Kinase Inhibitors
Molecular Biology
Cell Proliferation
Binding Sites
Biphenyl Compounds
Organic Chemistry
biology.organism_classification
0104 chemical sciences
010404 medicinal & biomolecular chemistry
030104 developmental biology
lcsh:Biology (General)
lcsh:QD1-999
Structural Homology, Protein
Moloney murine leukemia virus
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....3be62e640298faefca52dc7a531f5d2d
- Full Text :
- https://doi.org/10.3390/ijms20215410