Development of protein-ligand binding free energy prediction technique based on free energy inequality

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K12130
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 62010:Life, health and medical informatics-related
• Research Institution: Ritsumeikan University
• Principal Investigator: KIKUCHI Takeshi 立命館大学, 生命科学部, 教授 (90195206)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 結合自由エネルギー / ファインマン自由エネルギー不等式 / RISM理論 / 陽溶媒

Outline of Final Research Achievements

The purpose of the present research is to incorporate the effect of explicit solvent based on reference interaction site model (RISM) theory into the prediction method of the relative binding free energy based on Feynman free energy inequality （T. Ashida and T. Kikuchi, J. Comut-Aided Mol. Des. 27, 479 (2013), T. Ashida and T. Kikuchi, J. Comut-Aided Mol. Des.34, 647 (2020)）. In the previous studies, we used the implicit solvent model (MM-GB/SA method) for the calculation of the relative binding free energy and we obtained the results of the coefficient of determination, r2=0.72, ddGerror =1.04kcal/mol. The predictions of relative binding free energy were attempted for six inhibitors of Pim-1 kinase. The results indicate, r2=0.96、ΔΔGerror =0.32kcal/mol, that is, the results were widely improved compared with the previous studies in which the results show r2=0.72、ΔΔGerror =1.04kcal/mol.

Free Research Field

生物物理

Academic Significance and Societal Importance of the Research Achievements

本研究の基本的目標は、様々な疾病に関わるタンパク質とリガンドの相対的結合自由エネルギーを精度よく予測することである。それは、新薬開発の一番最初の重要な過程である。本研究では、ファインマンの自由エネルギー不等式に基づいた従来の方法に陽溶媒を取り入れることにより大幅な精度の向上を示す事ができた。このことは、将来創薬の現場において、結合自由エネルギーの高い精度での予測を可能とし、創薬過程を大きく効率化できることが期待される。