Biography
Biography: Tatsuya Takagi
Abstract
Since dengue virus (DENV) infection causes epidemics in tropics/subtropics, some times it causes a potentially lethal complication, dengue hemorrhagic fever. Unfortunately, there are no effective drugs or vaccines against this infection. Thus, development of drugs and vaccines against DENV is expected. Recently, we found SK-12, a novel NS2/NS3 protease inhibitor, by structure-based in Silico screening. In this study, we carried out some ligand-based in Silico screening studies forim proving the inhibitors based on the structure of SK-12. First, we defined a pharmacophore of SK-12, and then carried out a pharmacophore search using a compound database. Next, some fingerprints of SK-12 and of compounds in the same database were obtained and then a similarity search for the compounds was carried out. As the compound database, OCDD compound library provided by the University of Tokyo was used. All these calculations were operated by MOE (CCG Inc.). Finally, 80 compounds were extracted based on the docking score obtained by MOE Dock, from the compounds obtained by the abovementioned procedure. Viral replication assays and toxicity measurements of them by MTT assay showed that EC50=0.51µMfor compound 1 (SK-12,EC50=2.55µM),which indicates that compound 1 is more active than SK-12. However, in vitro protease assay of compound 1 showed no inhibitory activities against NS2B/NS3. Then we tried to search the target molecules of compound 1, which might be the novel target molecules of anti-DENV inhibitor.(This work was supported by Project MEET, Osaka University Graduate School of Medicine, and Mitsubishi Tanabe Pharma Corporation)