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Molecules 2014, 19(7), 9134-9159; doi:10.3390/molecules19079134

Investigation of the Flexibility of Protein Kinases Implicated in the Pathology of Alzheimer’s Disease

Centre for Biomolecular Sciences and School of Pharmacy, University of Nottingham, University Park, Nottingham NG7 2RD, UK
Current address: Evotec (UK) limited, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, UK.
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Received: 4 May 2014 / Revised: 16 June 2014 / Accepted: 19 June 2014 / Published: 30 June 2014
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
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Abstract

The pathological characteristics of Alzheimer’s Disease (AD) have been linked to the activity of three particular kinases—Glycogen Synthase Kinase 3β (GSK3β), Cyclin-Dependent Kinase 5 (CDK5) and Extracellular-signal Regulated Kinase 2 (ERK2). As a consequence, the design of selective, potent and drug-like inhibitors of these kinases is of particular interest. Structure-based design methods are well-established in the development of kinase inhibitors. However, progress in this field is limited by the difficulty in obtaining X-ray crystal structures suitable for drug design and by the inability of this method to resolve highly flexible regions of the protein that are crucial for ligand binding. To address this issue, we have undertaken a study of human protein kinases CDK5/p25, CDK5, ERK2 and GSK3β using both conventional molecular dynamics (MD) and the new Active Site Pressurisation (ASP) methodology, to look for kinase-specific patterns of flexibility that could be leveraged for the design of selective inhibitors. ASP was used to examine the intrinsic flexibility of the ATP-binding pocket for CDK5/p25, CDK5 and GSK3β where it is shown to be capable of inducing significant conformational changes when compared with X-ray crystal structures. The results from these experiments were used to quantify the dynamics of each protein, which supported the observations made from the conventional MD simulations. Additional information was also derived from the ASP simulations, including the shape of the ATP-binding site and the rigidity of the ATP-binding pocket. These observations may be exploited in the design of selective inhibitors of GSK3β, CDK5 and ERK2. View Full-Text
Keywords: active site pressurisation; kinase; structure-based drug design; protein flexibility; molecular dynamics active site pressurisation; kinase; structure-based drug design; protein flexibility; molecular dynamics
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This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Mazanetz, M.P.; Laughton, C.A.; Fischer, P.M. Investigation of the Flexibility of Protein Kinases Implicated in the Pathology of Alzheimer’s Disease. Molecules 2014, 19, 9134-9159.

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