Abstract
A significant portion of recent drug development efforts has been focused on protein kinases. More than a hundred different compounds are currently under clinical trials and nearly 30% of all the scientific articles in drug discovery are on protein kinase inhibitors. Protein kinases are very flexible targets and undergo significant conformational changes upon activation and during the catalytic cycle. This flexibility can be exploited in drug discovery. Some of the inactive states that emerge during the conformational changes are targeted by various inhibitors with a significant gain in selectivity. Here, we review the recent advances being made in understanding the details and the mechanism of these conformational changes thanks to the progress in molecular dynamics and free energy algorithms as well as to the availability of specialized computer hardware.
Keywords: Kinase, imatinib, molecular dynamics, metadynamics, allostery, signaling
Current Topics in Medicinal Chemistry
Title:New Insights in Protein Kinase Conformational Dynamics
Volume: 12 Issue: 17
Author(s): Giorgio Saladino and Francesco Luigi Gervasio
Affiliation:
Keywords: Kinase, imatinib, molecular dynamics, metadynamics, allostery, signaling
Abstract: A significant portion of recent drug development efforts has been focused on protein kinases. More than a hundred different compounds are currently under clinical trials and nearly 30% of all the scientific articles in drug discovery are on protein kinase inhibitors. Protein kinases are very flexible targets and undergo significant conformational changes upon activation and during the catalytic cycle. This flexibility can be exploited in drug discovery. Some of the inactive states that emerge during the conformational changes are targeted by various inhibitors with a significant gain in selectivity. Here, we review the recent advances being made in understanding the details and the mechanism of these conformational changes thanks to the progress in molecular dynamics and free energy algorithms as well as to the availability of specialized computer hardware.
Export Options
About this article
Cite this article as:
Saladino Giorgio and Luigi Gervasio Francesco, New Insights in Protein Kinase Conformational Dynamics, Current Topics in Medicinal Chemistry 2012; 12 (17) . https://dx.doi.org/10.2174/156802612804547407
DOI https://dx.doi.org/10.2174/156802612804547407 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...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
- Announcements
Related Articles
-
Unveiling mRNA Changes During Meiotic Progression and Pre-Implantation Development: Help from Large Animal Models
Current Pharmaceutical Design Effectiveness of Long-Term Macrolide Therapy in Cryptogenic Organising Pneumonia
Current Respiratory Medicine Reviews Pregnancy and Viral Hepatitis: Current Concepts
Current Pharmaceutical Design Radiation-Induced Extracranial Carotid Stenosis
Vascular Disease Prevention (Discontinued) Hypoxia-inducible Factor (HIF) in Hormone Signaling During Health and Disease
Cardiovascular & Hematological Agents in Medicinal Chemistry Dietary Modulation of Thymic Enzymes
Endocrine, Metabolic & Immune Disorders - Drug Targets Biomarkers of Alzheimer's Disease Risk in Peripheral Tissues; Focus on Buccal Cells
Current Alzheimer Research Angiotensin II: Role in Skeletal Muscle Atrophy
Current Protein & Peptide Science Monoclonal Antibodies in Solid Tumours
Current Clinical Pharmacology Physiology of Islet Engraftment
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Somatostatin: A Hormone for the Heart?
Current Vascular Pharmacology Establishment of Conditionally Immortalized Cell Lines with Specific Functions and its Application to Differential Gene Expression Analysis by DNA Microarray Technology
Current Pharmaceutical Analysis Editorial(Thematic Issue: Hypertension and Diabetes – Update in 2013)
Current Hypertension Reviews Potential Applications of Vasoactive Intestinal Peptide-Based Therapies on Transplantation
Endocrine, Metabolic & Immune Disorders - Drug Targets Environmentally Sensitive Paramagnetic and Diamagnetic Contrast Agents for Nuclear Magnetic Resonance Imaging and Spectroscopy
Current Topics in Medicinal Chemistry Characteristics of Patients with Hypopituitarism having Onset Symptoms of Pseudo-Intestinal Obstruction: A Case Report
Endocrine, Metabolic & Immune Disorders - Drug Targets Evidence for the Involvement of Lamins in Aging
Current Aging Science Cardiac Dysfunction in Rats with Dietary-Induced Insulin Resistance Associated with Pharmacologically-induced Dyslipidemia
Current Pharmaceutical Design Neuroprotection by Alpha 2-Adrenergic Agonists in Cerebral Ischemia
Current Neuropharmacology A Multicenter Study of IgE Sensitization to <i>Anisakis simplex</i> and Diet Recommendations
Endocrine, Metabolic & Immune Disorders - Drug Targets