3C-O1-0910 PDF
物理化学的アプローチによる蛋白質間相互作用阻害剤の探索
In the true molecular target-based drug discovery, hit, seed, and lead compounds should show high binding affinity and specific inhibition activity. To obtain the correct interaction profiles of small compounds with a target molecule, technical development of physicochemical approaches for the interactions is essential for the next generation molecular target-based drug discovery. Surface Plasmon Resonance (SPR), Isothermal Titration Calorimetry (ITC), and Differential Scanning Calorimetry (DSC) analyses are representative biophysical methods, because these analyses can monitor the direct binding of compounds, the thermal reaction of the binding, and conformational stability and change of protein with binding to compounds, respectively. In addition, it has recently been noted that Mass Spectroscopy (MS) is one of the attractive biophysical methods. However, the biophysical methods have been not yet wide-spread in the fields of the small molecule drug discovery. Therefore, it is urgent to develop the Quality Assessment techniques “Biophysical-QA” which utilize biophysical analyses in the small molecule drug discovery. We have carried out the small-molecule screening to obtain the inhibitors of protein-protein interaction (PPI) using SPR and ITC, and could select the hit compounds which inhibited the target PPI. Furthermore, MS analysis was utilized to characterize the PPI mechanisms and the hit compounds.