- 著者
- Chiduru Watanabe Hirofumi Watanabe Yoshio Okiyama Daisuke Takaya Kaori Fukuzawa Shigenori Tanaka Teruki Honma
- 出版者
- Chem-Bio Informatics Society
- 雑誌
- Chem-Bio Informatics Journal (ISSN:13476297)
- 巻号頁・発行日
- vol.19, pp.5-18, 2019-03-22 (Released:2019-03-23)
- 参考文献数
- 47
- 被引用文献数
- 26
We developed an automated FMO calculation protocol (Auto-FMO protocol) to calculate huge numbers of protein and ligand complexes, such as drug discovery targets, by an ab initio FMO method. The protocol performs not only FMO calculations but also pre-processing of input structures by homology modeling of missing atoms and subsequent MM-based optimization, as well as post-processing of calculation results. In addition, QM/MM optimization of complex structures, conformational searches of ligand structures in solvent, and MM-PBSA/GBSA calculations can be optionally carried out. In this paper, FMO calculations for 149 X-ray complex structures of estrogen receptor α and p38 MAP kinase were performed at the K computer and in-house PC cluster server by using the Auto-FMO protocol. To demonstrate the usefulness of the Auto-FMO protocol, we compared the ligand binding interaction energies by the Auto-FMO protocol with those of manually prepared data. In most cases, the data calculated by the Auto-FMO protocol showed reasonable agreement with the manually prepared data. Further improvement of the protocol is necessary for the treatment of ionization and tautomerization at the structure preparation stage, because some outlier data were observed due to these issues. The Auto-FMO protocol provides a powerful tool to deal with huge numbers of complexes for drug design, as well as for the construction of the FMO database (http://drugdesign.riken.jp/FMODB/) released in 2019.
- 著者
- Katsuhiko Sekimata Tomohiro Sato Naoki Sakai Hisami Watanabe Chiemi Mishima-Tsumagari Tomonori Taguri Takehisa Matsumoto Yoshifumi Fujii Noriko Handa Teruki Honma Akiko Tanaka Mikako Shirouzu Shigeyuki Yokoyama Kohei Miyazono Yoshinobu Hashizume Hiroo Koyama
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Chemical and Pharmaceutical Bulletin (ISSN:00092363)
- 巻号頁・発行日
- vol.67, no.3, pp.224-235, 2019-03-01 (Released:2019-03-01)
- 参考文献数
- 17
- 被引用文献数
- 11
Mutant activin receptor-like kinase-2 (ALK2) was reported to be closely associated with the pathogenesis of fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG), and therefore presents an attractive target for therapeutic intervention. Through in silico virtual screenings and structure–activity relationship studies assisted by X-ray crystallographic analyses, a novel series of bis-heteroaryl pyrazole was identified as potent inhibitors of ALK2 (R206H). Derived from in silico hit compound RK-59638 (6a), compound 18p was identified as a potent inhibitor of ALK2 (R206H) with good aqueous solubility, liver microsomal stability, and oral bioavailability.