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.
|Date of Award||1 Apr 2016|
- University Of Strathclyde
|Sponsors||University of Strathclyde|
|Supervisor||Nick Tomkinson (Supervisor) & Simon MacKay (Supervisor)|