The development of novel therapeutic drugs targeting the active site of a protein requires detailed knowledge of the molecular structure. Using small angle X-ray (SAXS) or neutron scattering it is possible to reconstruct the structure of the targeted protein at low resolution before and after complexation with the drug. Here SAXS was employed to study the structural changes of the xanthine oxidoreductase (XOR) under complexation with novel purine analog as effective inhibitor of the XOR enzyme activity (Ki =0.55 microM). XOR is a key enzyme of purine catabolism, which is involved in the pathogenesis of hyperuricemia, gout and oxidative stress-related cardiovascular diseases [1, 2]. Currently, there are two XOR inhibitors available at the market – purine based allopurinol and nonpurine febuxostat. Since these both drugs possess significant side effects [3], the search for new XOR inhibitors continues.
The initial results revealed that the studied purine analog influenced the structure of XOR thus binding affinity was rather high. This effect can be explained by considering the geometry of the active site of XOR and the overall shape of the small purine analog. Further experiments are planned to clarify mechanism of XOR inhibition by this purine analog. Based on these structure-activity relationships, improved analogs will be designed.
This work was supported by #RVO:61388963 and MoE # NPU I, LO 1302