Back to Search
Start Over
Steered molecular dynamics simulations reveal the likelier dissociation pathway of imatinib from its targeting kinases c-Kit and Abl.
- Source :
-
PloS one [PLoS One] 2009 Dec 24; Vol. 4 (12), pp. e8470. Date of Electronic Publication: 2009 Dec 24. - Publication Year :
- 2009
-
Abstract
- Development of small molecular kinase inhibitors has recently been the central focus in drug discovery. And type II kinase inhibitors that target inactive conformation of kinases have attracted particular attention since their potency and selectivity are thought to be easier to achieve compared with their counterpart type I inhibitors that target active conformation of kinases. Although mechanisms underlying the interactions between type II inhibitors and their targeting kinases have been widely studied, there are still some challenging problems, for example, how type II inhibitors associate with or dissociate from their targeting kinases. In this investigation, steered molecular dynamics simulations have been carried out to explore the possible dissociation pathways of typical type II inhibitor imatinib from its targeting protein kinases c-Kit and Abl. The simulation results indicate that the most favorable pathway for imatinib dissociation corresponds to the ATP-channel rather than the relatively wider allosteric-pocket-channel, which is mainly due to the different van der Waals interaction that the ligand suffers during dissociation. Nevertheless, the direct reason comes from the fact that the residues composing the ATP-channel are more flexible than that forming the allosteric-pocket-channel. The present investigation suggests that a bulky hydrophobic head is unfavorable, but a large polar tail is allowed for a potent type II inhibitor. The information obtained here can be used to direct the discovery of type II kinase inhibitors.
- Subjects :
- Adenosine Triphosphate metabolism
Benzamides
Imatinib Mesylate
Ion Channels metabolism
Ligands
Models, Molecular
Piperazines chemistry
Piperazines pharmacology
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors pharmacology
Protein Structure, Secondary
Proto-Oncogene Proteins c-abl chemistry
Proto-Oncogene Proteins c-kit chemistry
Pyrimidines chemistry
Pyrimidines pharmacology
Thermodynamics
Molecular Dynamics Simulation
Piperazines metabolism
Protein Kinase Inhibitors metabolism
Proto-Oncogene Proteins c-abl antagonists & inhibitors
Proto-Oncogene Proteins c-abl metabolism
Proto-Oncogene Proteins c-kit antagonists & inhibitors
Proto-Oncogene Proteins c-kit metabolism
Pyrimidines metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 4
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 20041122
- Full Text :
- https://doi.org/10.1371/journal.pone.0008470