2-B-P-086 〇藤井 咲衣、八木 珠麗菜、村山 尚、櫻井 隆、小林 琢也 Sae Fujii, Shurina Yagi, Takashi Murayama, Takashi Sakurai, Takuya Kobayashi 順天堂大・医・薬理学講座 Department of Pharmacology, Faculty of Medicine, Juntendo University The type 1 ryanodine receptor (RyR1) is a Ca2+ release channel in skeletal muscle. RyR1 is also expressed in brain and nonmuscle tissues and hyperactivation of RyR1 is implicated not only in skeletal muscle diseases, such as malignant hyperthermia, but also in diseases of the brain and other tissues. Therefore, pharmacological inhibition of RyR1 may have a therapeutic potential for various diseases. We have developed Cpd1, a selective RyR1 inhibitor for the treatment of malignant hyperthermia, but it has disadvantages of low oral efficacy and short half-life. To identify novel inhibitors with improved properties, in this study, we aimed to establish in silico screening platform based on the Cpd1-RyR1 complex structure predicted by molecular dynamics simulations. First, we performed amino acid substitutions and Cpd1 modifications on the computer and ran simulations with these modifications. Second, based on these results, amino acid substitution mutants and Cpd1 derivatives were evaluated by biochemical experiments. The results showed that the molecular dynamics simulations were in good agreement with the biochemical experiments. The results of in silico screening with the platform will be presented.