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Michael P. Mazanetz is a final year PhD student in medicinal chemistry under the supervision of Prof. Peter Fischer in the School of Pharmacy at the University of Nottingham, working on the design and synthesis of kinase inhibitors for the treatment of neurodegenerative diseases. His main interests are in utilising and development of computational methods to progress drug design and in the synthesis of drug-like small molecules. He previously completed BSc and MSc degrees in organic chemistry at the University of Western Australia and has worked as a medicinal chemist in the UK pharmaceutical sector for several years, most recently with Eli Lilly in Windlesham, Surrey.
He is a member of the Royal Society of Chemistry and a chartered chemist with the Royal Australian Chemical Institute. He is an active member in the molecular modelling community where he frequently presents his work, and has won the 2007 poster prize at the BS and MGMS conference `Bringing Together Biomolecular Simulation and Experimental Design’, the 2007 poster prize at the CCPB conference ‘Biomolecular Simulation 2007’ meeting, the 2006 poster prize at the BS Life Changing Molecules Symposium, and the 2006 presentation prize at the SCI Conference 'Modelling the Properties and Behaviour of Molecules'. He was the recipient of the first eCheminfo Oxford Bursary Award in 2006.
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Application of CADD methodologies in the structure-based design of selective kinase inhibitors
Michael P. Mazanetz, Ian M. Withers, Charles A. Laughton and Peter M. Fischer, Centre for Biomolecular Sciences and School of Pharmacy, University of Nottingham
The pathological characteristics of Alzheimer’s Disease (AD) have recently been linked to glycogen synthase kinase 3β (GSK-3β) [1]. It has been shown that inhibiting this kinase with ATP-competitive small molecules results in reduced tau phosphorylation (a hallmark of AD). However, the design of selective, potent and drug-like inhibitors is still an on-going challenge. Most of the small molecule GSK-3β inhibitors described to date target the highly conserved kinase ATP-binding pocket. Current structure-based design methods do not adequately take into account protein flexibility but rely on static crystal structures.
In this presentation we introduce the strategy we have employed to design selective kinase inhibitors. We will present an application of a new computational drug design methodology, Active Site Pressurization (ASP), which is used to examine the intrinsic flexibility of the ATP-binding pocket [2,3]. A 3D quantitative structure-activity relationship (QSAR) model derived from this method to predict the activity of potential kinase inhibitors using both ligand- and receptor-based design strategies will be discussed. This talk will also describe the virtual library design and screening using molecular docking methods utilised in our drug discovery process.
References
1. Mazanetz, M. P., Fischer, P. M., Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases. Nat Rev Drug Discov 2007, 6, (6), 464-79.
2. Withers, I. M., Mazanetz, M. P., Wang, H., Fischer, P. M., Laughton, C. A., Active Site Pressurisation: A New Tool for Structure-Guided Design. J. Chem. Inf. Mod., 2008 in press.
3. Mazanetz, M. P., Withers, I. M., Laughton, C. A., Fischer, P. M., Exploiting glycogen synthase kinase 3β flexibility in molecular recognition. Biochem. Soc. Trans. 2008, 36, (1), 55-58.
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