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A Back-to-Front Fragment-Based Drug Design Search Strategy Targeting the DFG-Out Pocket of Protein Tyrosine Kinases.

ABSTRACT: We present a straightforward process for the discovery of novel back pocket-binding fragment molecules against protein tyrosine kinases. The approach begins by screening against the nonphosphorylated target kinase with subsequent counterscreening of hits against the phosphorylated enzyme. Back pocket-binding fragments are inactive against the phosphorylated kinase. Fragment molecules are of insufficient size to span both regions of the ATP binding pocket; thus, the outcome is binary (back pocket-binding or hinge-binding). Next, fragments with the appropriate binding profile are assayed in combination with a known hinge-binding fragment and subsequently with a known back pocket-binding fragment. Confirmation of back pocket-binding by Yonetani-Theorell plot analysis progresses candidate fragments to crystallization trials. The method is exemplified by a fragment screening campaign against vascular endothelial growth factor receptor 2, and a novel back pocket-binding fragment is presented.

SUBMITTER: Iwata H

PROVIDER: S-EPMC4025632 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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A Back-to-Front Fragment-Based Drug Design Search Strategy Targeting the DFG-Out Pocket of Protein Tyrosine Kinases.

Iwata Hidehisa H Oki Hideyuki H Okada Kengo K Takagi Terufumi T Tawada Michiko M Miyazaki Yasushi Y Imamura Shinichi S Hori Akira A Lawson J David JD Hixon Mark S MS Kimura Hiroyuki H Miki Hiroshi H

ACS medicinal chemistry letters 20120228 4

We present a straightforward process for the discovery of novel back pocket-binding fragment molecules against protein tyrosine kinases. The approach begins by screening against the nonphosphorylated target kinase with subsequent counterscreening of hits against the phosphorylated enzyme. Back pocket-binding fragments are inactive against the phosphorylated kinase. Fragment molecules are of insufficient size to span both regions of the ATP binding pocket; thus, the outcome is binary (back pocket ...[more]

PMID: 24900475

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Project description:BACKGROUND: Back pain impacts on a significant proportion of the Australian population over the life course and has high prevalence rates among women, particularly in older age. Back pain care is characterised by multiple practitioner and self-prescribed treatment options, and the out-of-pocket costs associated with consultations and self-prescribed treatments have not been examined to date. OBJECTIVE: To analyse the extent of health care practitioner consultations and self-prescribed treatment for back pain care among Australian women, and to assess the self-reported costs associated with such usage. METHODS: Survey of 1,310 women (response rate 80.9%) who reported seeking help for back pain from the '1946-51 cohort' of the Australian Longitudinal Study on Women's Health. Women were asked about their use of health care practitioners and self-prescribed treatments for back pain and the costs associated with such usage. RESULTS: In the past year 76.4% consulted a complementary and alternative practitioner, 56% an allied health practitioner and 59.2% a GP/medical specialist. Overall, women consulted with, on average, 3.0 (SD = 2.0) different health care practitioners, and had, on average, 12.2 (SD = 9.7) discrete health care practitioner consultations for back pain. Average self-reported out-of-pocket expenditure on practitioners and self-prescribed treatments for back pain care per annum was AU$873.10. CONCLUSIONS: Multiple provider usage for various but distinct purposes (i.e. pain/mobility versus anxiety/stress) points to the need for further research into patient motivations and experiences of back pain care in order to improve and enhance access to and continuity of care. Our results suggest that the cost of back pain care represents a significant burden, and may ultimately limit women's access to multiple providers. We extrapolate that for Australian working-age women, total out-of-pocket expenditure on back pain care per annum is in excess of AU$1.4 billion, thus indicating the prominence of back pain as a major economic, social and health burden.

Dataset Information

A Back-to-Front Fragment-Based Drug Design Search Strategy Targeting the DFG-Out Pocket of Protein Tyrosine Kinases.

Publications

A Back-to-Front Fragment-Based Drug Design Search Strategy Targeting the DFG-Out Pocket of Protein Tyrosine Kinases.

Similar Datasets

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