Thesis
Building a rational model for the identification of allosteric sites
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2016
- Thesis identifier
- T14284
- Person Identifier (Local)
- 201266694
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Allostery is the regulation of protein function, structure and/or flexibility that is induced by the binding of a ligand at a site distinct from the orthosteric site.1, 2 Interaction of a small molecule with these sites can bring greater selectivity as they are not conserved within a family and therefore could lead to new opportunities in drug discovery. Unfortunately, no definitive technique has yet been identified to distinguish these allosteric sites. Al-Shar'i developed a new technique using a combination of fluctuation analysis, cross correlation, simple intrasequence difference (SID) and energy analysis.3 A potential site has been determined for the protein kinase DYRK2 using this technique. The potential allosteric pocket was studied through a virtual screen which gave a hit that was successfully prepared and showed good selectivity for DYRK2 over DYRK1A by Differential Scanning Fluorimetry (DSF). This oxyamidine hit was further investigated through a structure activity relationship (SAR) which enabled the synthesis of three compounds that showed a higher stabilization than the initial hit (Tm > 1.2 °C). A second library was synthesized based on the same core, but with an amide functionality instead of an oxyamidine. From this new library, a SAR study was also carried out. This led to the synthesis of five analogues that have shown great binding activity (IC50 < 240nM) and selectivity for DYRK2.
- Resource Type
- DOI
- Date Created
- 2016
- Former identifier
- 9912538565002996
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