Ligand discovery based on biophysical analyses

2015 Fiscal Year Final Research Report

• Project/Area Number: 25249115
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biofunction/Bioprocess
• Research Institution: The University of Tokyo
• Principal Investigator: Tsumoto Kouhei 東京大学, 工学(系)研究科(研究院), 教授 (90271866)
• Co-Investigator(Kenkyū-buntansha): NAGATOISHI Satoru 東京大学, 大学院工学系研究科, 助教 (30550248)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 低分子創薬 / 熱力学解析 / フラグメントスクリーニング / 相互作用

Outline of Final Research Achievements

We studied fragment-based drug discovery based on the biophysical methods, including isothermal titration calorimetry (ITC), surface plasmon resonance (SPR), and differential scanning calorimetry (DSC). The hit compounds bound specifically to target proteins; the interactions between compounds and the targets were validated using these biophysical measurements and the binding mechanisms have been characterized thermodynamically. We carried out X-ray crystallographic analyses and in silico docking simulation to discuss the thermodynamics of the interactions. The crystal structure and docking simulation supported thermodynamic data. Moreover, one hit compound was optimized to bind strongly to the target protein, of which dissociation constant showed sub-micro molar. This research provides a novel rational strategy to obtain the true-hit compounds through screening small molecule compounds.

Free Research Field

蛋白質工学、生命物理化学