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.
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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 |
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