薬剤耐性菌の制圧に向けた創薬の新展開 ―アミノ酸マッピングによる新規阻害剤の効率的合成―

2026-09-30 大阪大学産業科学研究所

図1 アミノ酸マッピングの概念図。AAM記述子は化合物周辺に計算される20種類のアミノ酸残基ごとの3次元存在分布であり、タンパク質の標的部位に結合しうる化合物の特徴が表現されています。

＜関連情報＞

• https://www.sanken.osaka-u.ac.jp/achievement/release/20260930_02.html
• https://www.nature.com/articles/s41429-026-00953-9

アミノ酸マッピングに基づいた足場選択と、1200万以上の化合物からなる仮想ライブラリからのヒスチジンキナーゼ阻害剤のヒット同定 Amino acid mapping–guided scaffold selection and hit identification of histidine kinase inhibitors from a virtual library of over 12 million compounds

Teruhiko Ishikawa, Yoko Eguchi, Toshihide Okajima, Masayuki Igarashi, Shino Ohira, Kyosuke Tsumura, Kazumasa Sakurai, Yoshimasa Ishizaki, Chigusa Hayashi, Shammi Akter, Jiro Nakayama, Chie Kohayakawa, Akiyoshi Tani, Naoki Sawa, Takaomi Katsumoto, Fumiya Matsumoto, Jun-Ichi Haruta & Ryutaro Utsumi
The Journal of Antibiotics  Published:30 September 2026
DOI:https://doi.org/10.1038/s41429-026-00953-9

Abstract

Waldiomycin is a natural product originally isolated from actinomycete extracts. It inhibits histidine kinases (HKs), which are essential components of bacterial two-component signal transduction systems, by targeting the conserved H-box region and suppressing autophosphorylation. Here, we identified novel HK inhibitors using amino acid mapping (AAM)-based virtual screening. We compared the AAM descriptor of the naphthoquinone moiety of waldiomycin, which directly interacts with the H-box region, with those of approximately 12 million commercially available compounds and identified 714 candidates with similar descriptor values. From these candidates, we selected 9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one as a promising and structurally distinct scaffold and synthesized 15 derivatives. The inhibitory activities of these derivatives were evaluated against the HKs WalK, VicK, and EnvZ. Three 4H-pyrido[1,2-a]pyrimidin-4-one derivatives (FF-054, FF-055, and FF-060) exhibited potent inhibitory activity, with IC₅₀ values ranging from 4.39 to 259 µM. Notably, the IC₅₀ values of these compounds increased three- to six-fold against the EnvZ S242A mutant, in which the conserved H-box residue is substituted. Furthermore, nuclear magnetic resonance (NMR) analysis using the EnvZ DHp domain (residues 223–289, encompassing the H-box region) confirmed direct interaction with this domain. Taken together, these results demonstrate that pyrido[1,2-a]pyrimidin-4-one derivatives FF-054, FF-055, and FF-060 are novel HK inhibitors that target the H-box region. This study represents the first successful application of AAM-based screening to identify HK inhibitors targeting this highly conserved region.