Abstract
Large-scale (∼36,000 atoms) long-time (30 ns each) molecular dynamics (MD) simulations on the complex of imatinib and 16 common mutants of the ABL tyrosine kinase domain have been performed to study the imatinib resistance mechanisms at the atomic level. MD simulations show that long time computational simulations could offer insight information that static models, simple homology modeling methods, or short-time simulations cannot provide for the BCR-ABL imatinib resistance problem. Three possible types of mutational effects from those mutants are found: the direct effect on the contact interaction with imatinib (e.g. some P-loop mutations), the effect on the conformation of a remote region contacting with imatinib (e.g. T315I), and the effect on interaction between two regions within the BCR-ABL domain (e.g. H396P). Insights of possible imatinib resistance mechanisms, not consistent with current consensus, are revealed from various analyses and our findings suggest that drugs with different binding modes may be necessary to overcome the drug resistance due to T315I and other mutations. The relevant patents are discussed.
Keywords: BCR-ABL, imatinib resistance, molecular dynamics simulation, MD simulation
Recent Patents on Anti-Cancer Drug Discovery
Title: Basis for Resistance to Imatinib in 16 BCR-ABL Mutants as Determined Using Molecular Dynamics
Volume: 4 Issue: 2
Author(s): Tai-Sung Lee, Steven J. Potts and Maher Albitar
Affiliation:
Keywords: BCR-ABL, imatinib resistance, molecular dynamics simulation, MD simulation
Abstract: Large-scale (∼36,000 atoms) long-time (30 ns each) molecular dynamics (MD) simulations on the complex of imatinib and 16 common mutants of the ABL tyrosine kinase domain have been performed to study the imatinib resistance mechanisms at the atomic level. MD simulations show that long time computational simulations could offer insight information that static models, simple homology modeling methods, or short-time simulations cannot provide for the BCR-ABL imatinib resistance problem. Three possible types of mutational effects from those mutants are found: the direct effect on the contact interaction with imatinib (e.g. some P-loop mutations), the effect on the conformation of a remote region contacting with imatinib (e.g. T315I), and the effect on interaction between two regions within the BCR-ABL domain (e.g. H396P). Insights of possible imatinib resistance mechanisms, not consistent with current consensus, are revealed from various analyses and our findings suggest that drugs with different binding modes may be necessary to overcome the drug resistance due to T315I and other mutations. The relevant patents are discussed.
Export Options
About this article
Cite this article as:
Lee Tai-Sung, Potts J. Steven and Albitar Maher, Basis for Resistance to Imatinib in 16 BCR-ABL Mutants as Determined Using Molecular Dynamics, Recent Patents on Anti-Cancer Drug Discovery 2009; 4 (2) . https://dx.doi.org/10.2174/157489209788452867
DOI https://dx.doi.org/10.2174/157489209788452867 |
Print ISSN 1574-8928 |
Publisher Name Bentham Science Publisher |
Online ISSN 2212-3970 |
Call for Papers in Thematic Issues
Novel anti-cancer drugs in photoimmunotherapy management: from bench to translational research
In recent years, traditional cancer treatments, such as surgery, chemotherapy, and radiation treatment, etc., may damage the pathological tissue and normal cells. The ideal tumor treatment should be noninvasive, eliminating the primary tumor, making the body produce systemic tumor-specific immunity, eliminating metastases, and having less /no side effects. Recent Patents ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Toxicity and Relative Biological Effectiveness of Alpha Emitting Radioimmunoconjugates
Current Radiopharmaceuticals Should We Develop an Inhaled Anti-pneumococcal Vaccine for Adults?
Current Medicinal Chemistry - Anti-Infective Agents Making Sense of Molecular Signatures in The Immune System
Combinatorial Chemistry & High Throughput Screening ADAM Metalloproteinases as Potential Drug Targets
Current Medicinal Chemistry Meet Our Editorial Board Member
Current Cancer Drug Targets Transcription Factors as Potential Targets for Therapeutic Drugs
Current Pharmaceutical Biotechnology Paris polyphylla: Chemical and Biological Prospectives
Anti-Cancer Agents in Medicinal Chemistry Interferon-Beta Therapy Monitoring in Multiple Sclerosis Patients
Endocrine, Metabolic & Immune Disorders - Drug Targets Targeting Receptor Tyrosine Kinases Using Monoclonal Antibodies: The Most Specific Tools for Targeted-Based Cancer Therapy
Current Drug Targets Targeting Sphingosine-1-Phosphate in Hematologic Malignancies
Anti-Cancer Agents in Medicinal Chemistry Flavonoids as Anticancer Agents: Recent Progress and State of the Art?
Current Organic Chemistry Naphthoflavones as Antiproliferative Agents: Design, Synthesis and Biological Evaluation
Anti-Cancer Agents in Medicinal Chemistry Serpins for Diagnosis and Therapy in Cancer
Cardiovascular & Hematological Disorders-Drug Targets Paraneoplastic Neurological Syndromes - Diagnosis and Management
Current Pharmaceutical Design Major Challenges for Gene Therapy of Thalassemia and Sickle Cell Disease
Current Gene Therapy Glycosidated Phospholipids – a Promising Group of Anti-Tumour Lipids
Anti-Cancer Agents in Medicinal Chemistry The Culture-Repopulating Ability Assays and Incubation in Low Oxygen: A Simple Way to Test Drugs on Leukaemia Stem or Progenitor Cells
Current Pharmaceutical Design Nanotechnology, A Tool for Diagnostics and Treatment of Cancer
Current Topics in Medicinal Chemistry Inhibitory Effect of Fruit Juices on the Doxorubicin Metabolizing Activity of Carbonyl Reductase 1
Drug Metabolism Letters Population Diversity and its Relationship with Infectious and Tumor Diseases
Current Immunology Reviews (Discontinued)