タンパク質–リガンド間相互作用解析における水素原子構造の重要性

～量子化学計算データに基づく精緻な論理創薬へ向けた取り組み～

抄録

Protonation states of ionizable amino acid residues (e.g., Asp, Glu, Lys) on a ligand-binding pocket are critically important information for structure-based drug design. However, in general, hydrogen atoms including protons on the amino acid residues are not determined by X-ray crystallography in PDB entries with resolution ca. 1.0~3.0Å. For example, we have generally treated Asp and Glu as deprotonated states at the physiological condition (pH 7.4). There are concerns that a ligand-binding mode depends on the wrong protonation states of amino acid residues in a protein. If we use a protein structure with the wrong protonation states, drug design would be misled by its incorrect ligand-binding mode. In this regard, we must appropriately assign such protonation and tautomerization states by pKa calculations and the visual inspection of X-ray crystal structures and their electron densities. In addition, we should confirm whether the predicted protonation states of complex are energetically stable. Thus, we will attempt to estimate the validity of the protonation states on protein by quantum chemical calculations based on fragment molecular orbital (FMO) method. Recently, our group has developed FMO database (https://drugdesign.riken.jp/FMODB/) to accumulate FMO data. Experimental researchers such as structural biologists and medicinal chemists can quantitatively understand molecular recognition and easily use FMO data to help in drug design.