Molecular Dynamics of Protein Kinase-Inhibitor Complexes: A Valid Structural Information

Author(s): Julio Caballero, Jans H. Alzate-Morales

Journal Name: Current Pharmaceutical Design

Volume 18 , Issue 20 , 2012

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Protein kinases (PKs) are key components of protein phosphorylation based signaling networks in eukaryotic cells. They have been identified as being implicated in many diseases. High-resolution X-ray crystallographic data exist for many PKs and, in many cases, these structures are co-complexed with inhibitors. Although this valuable information confirms the precise structure of PKs and their complexes, it ignores the dynamic movements of the structures which are relevant to explain the affinities and selectivity of the ligands, to characterize the thermodynamics of the solvated complexes, and to derive predictive models. Atomistic molecular dynamics (MD) simulations present a convenient way to study PK-inhibitor complexes and have been increasingly used in recent years in structure-based drug design. MD is a very useful computational method and a great counterpart for experimentalists, which helps them to derive important additional molecular information. That enables them to follow and understand structure and dynamics of protein-ligand systems with extreme molecular detail on scales where motion of individual atoms can be tracked. MD can be used to sample dynamic molecular processes, and can be complemented with more advanced computational methods (e.g., free energy calculations, structure-activity relationship analysis). This review focuses on the most commonly applications to study PK-inhibitor complexes using MD simulations. Our aim is that researchers working in the design of PK inhibitors be aware of the benefits of this powerful tool in the design of potent and selective PK inhibitors.

Keywords: Molecular dynamics, protein kinases, docking, free energy calculations, 4D-QSAR, protein phosphorylation, X-ray crystallographic data, PK inhibitors, threonine residues, signal proteins

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Article Details

Year: 2012
Published on: 15 May, 2012
Page: [2946 - 2963]
Pages: 18
DOI: 10.2174/138161212800672705
Price: $65

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