成果報告書詳細
管理番号20120000001219
タイトル*平成23年度中間年報 「創薬加速に向けたタンパク質機能解析基盤技術開発」(一般社団法人バイオ産業情報化コンソーシアム、国立大学法人京都大学、国立大学法人東京大学、国立大学法人大阪大学蛋白質研究所、独立行政法人産業技術総合研究所)
公開日2014/8/28
報告書年度2011 - 2011
委託先名一般社団法人バイオ産業情報化コンソーシアム 国立大学法人京都大学 国立大学法人東京大学大学院薬学系研究科 国立大学法人大阪大学蛋白質研究所 独立行政法人産業技術総合研究所
プロジェクト番号P08005
部署名バイオテクノロジー・医療技術部
和文要約
英文要約Title: Structural Guided Drug Development (FY2008-FY2012) FY2011 Annual Report
 The water channel of human-AQP4 was found to have no effect by acetazolamide which had been confirmed to be an effective blocker for rat-AQP4 and mouse-AQP4. For developing better blocker for both human-AQP4 and rat-AQP4, the structure of aquaporin-4 and acetazolamide complex was analyzed and the binding structure of acetazolamide was clearly discriminated in the channel. By improving resolution of structure analysis of gap junction channel connexion-26, elaborate structures of the plug as well as the cytoplasmic construction were observed in the density map of the gap junction channel. Structures of H+, K+-ATPase binding with SCH28080, which was inhibitor of the pump, and of H+, K+-ATPase with rubidium ions were analyzed by electron crystallography. Structure of the C-terminal region of NavSulP grafted into the C-terminus of a NaK channel was analysed and showed that the cytosolic C-terminal region accelerated channel inactivation.
 A wide variety of compound library is currently available and it is relatively easy to obtain active compounds by high throughput screening. But the affinities of initial screened compounds are usually too low and it is necessary to improve the compounds by the chemical modification. In such cases, pharmacophore (epitope) information of the compounds plays a key role for next modification step. Therefore, many kinds of chemists would highly appreciate for simple and accurate experimental pharmacophore information. Here, we developed a novel and simple NMR approach for pharmacophore mapping experiments, which utilizes the difference between the longitudinal relaxation rates of ligand protons with and without irradiation of the target protein protons. We applied this method to identify the binding portions of ligand molecules for a number of ligand-protein interaction systems and obtained results consistent with the estimated proton density around each ligand proton. An application experiment for a low-affinity lead compound indicates that our quantitative pharmacophore mapping provides a useful guideline for lead optimization and fragment growing and/or linking in a Fragment-based drug design (FBDD) strategy.
 We developed software for structure-based drug screening, ligand-based drug screening and a compound database. These computer programs were released as “myPresto version 4.205” on Oct 2011. We developed a protein-ligand docking method based on NMR experimental data of ligand in solution and the prediction accuracy was increased by twice comparing to the ordinary protein-ligand docking study. We developed a screening procedure for G-protein coupled receptors (GPCR). In this procedure, multiple template structures of the GPCR were generated and the most reliable structure was selected by using the universal active probe (UAP). The UAP was developed by us last year and it is a set of drug-like compounds. This procedure was applied to a peptide receptor GPCR and some active small molecules those mimic the ligand peptide were found. We developed a high-performance molecular dynamics (MD) simulation program using the general-purpose graphic processor units (GPGPU). Finally, the multi-caninocal MD simulation that was developed by us was applied to a coupled folding and binding problem for protein-protein complex systems and the reaction mechanism was analyzed.
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