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Shaginian, Alex, Whitby, Landon R., Hong, Sukwon, Hwang, Inkyu, Farooqi, Bilal, Searcey, Mark 
ORCID: https://orcid.org/0000-0003-2273-8949, Chen, Jiandong, Vogt, Peter K. and Boger, Dale L.
(2009)
Design, synthesis, and evaluation of an a-helix mimetic library targeting protein-protein interactions.
Journal of the American Chemical Society, 131 (15).
pp. 5564-5572.
Abstract
The design and solution-phase synthesis of an a-helix mimetic library as an integral component of a small-molecule library targeting protein - protein interactions are described. The iterative design, synthesis, and evaluation of the candidate a-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 × 20 × 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i + 4, i + 7 amino acid side chains of an a-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid-liquid extractions for purification on a scale that insures its long-term availability for screening campaigns. Screening of the library for inhibition of MDM2/p53 binding not only identified the lead a-helix mimetic upon which the library was based, but also suggests that a digestion of the initial screening results that accompany the use of such a comprehensive library can provide insights into the nature of the interaction (e.g., an a-helix mediated protein-protein interaction) and define the key residues and their characteristics responsible for recognition. © 2009 American Chemical Society.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | small,hdm2,iminodiacetic acid libraries,in-vivo,olefin metathesis,antagonists,phase combinatorial synthesis,small-molecule antagonists,reaction,parallel synthesis,p53-mdm2 interaction,terephthalamide derivatives,organic-molecules |
| Faculty \ School: | Faculty of Science > School of Pharmacy (former - to 2024) |
| UEA Research Groups: | Faculty of Science > Research Groups > Medicinal Chemistry (former - to 2017) Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021) |
| Related URLs: | |
| Depositing User: | Rachel Smith |
| Date Deposited: | 17 Mar 2011 14:22 |
| Last Modified: | 24 Sep 2024 09:19 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/26558 |
| DOI: | 10.1021/ja810025g |
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