Drug Discovery and Medical Technology Platforms to Support ...

Wide-ranging technology platforms are necessary for the research and development of new drugs and medical technologies, and the technology platforms themselves are also innovating in step with progress in life science research. In drug discovery research, we create the seeds for drug discovery through a range of screenings including identification and analysis of the proteins that cause diseases and other drug discovery targets, aiming for optimization through medicinal chemistry and then proceeding to preclinical trial. Consequently, in drug discovery and medical technology research, the work is not concluded by a single research laboratory, but it is advanced by organizational strategy directing a wide range of technology platforms. The Drug Discovery and Medical Technology Platforms have responded by structuring each drug discovery platform unit and rebuilding the drug discovery research functions already extant at the RIKEN BASE (Bioinformatics And Systems Engineering) Division which studies the life science within RIKEN Yokohama Institute.

We have pinpointed three research and development domains for implementing drug discovery and medical technology. As well as upgrading and structuring these domains we are taking steps for collab-orative measures with external organizations. They are the basic research domain for identifying and analyzing drug discovery targets, the investigative research and development domain for screening and optimizing compounds, and the TR (translational) support domain for clinical studies and for the preclini-cal studies that conduct safety and security evaluations in order to advance to the stage of clinical studies (See diagram below).

At the Drug Discovery and Medical Technology Platforms, we are in charge of updating compound libraries, the explorative research and development areas in the basic research domain including interac-tive and structural analysis of complexes, as well as the function of building bridges to the TR support domain.

　To cover these research and development domains, we have established seven drug discovery units and four cutting-edge training platforms, and we have outsourced the technology platforms that do not exist within the research institute. With respect to the TR support domain, we are collaborating with the Tohoku University School of Medicine and others.

Drug Discovery and Medical Technology Platforms toSupport One-Stop, Speedy Research and Development

Chemical Bank Unit:Screening with Natural Compounds

　The forte of the Chemical Bank Unit is the 24,000 natural compounds collected in the NPdepo natural compound depository, and its database. As well as independently collecting and storing microbial secondary metabolites, the Bank promotes the depository of natural compounds by making the database of compounds available to the public on the Internet. In addition, the Bank is undertaking screening research for interaction between natural compounds and proteins by developing and using a chemical chip capable of detecting and measuring trace amounts.

＞＞Details can be found here

Drug Discovery Computational Chemistry Platform Unit:High-precision In Silico Screening Using the Latest Modeling Theories and Statistical Theories

　At the Drug Discovery Computational Chemistry Platform Unit, we implement high-precision in silico screening through the latest in both modeling theories and statistical theories, using the three-dimensional structure of target proteins and information about known inhibitors. Our strong points are machine learning of experimental data such as the results of WET screening, and facilitating optimized designs for ADMET etc.

＞＞Details can be found here

Biochemical and Cell-based Drug Discovery Platform Unit:Highly Sensitive and Fast Screening of Inhibitory Compounds

　At the Biochemical and Cell-based Drug Discovery Platform Unit, we use proprietary assay systems or automated robots to carry out cell-based compound potency estimates and in vitro biochemical estimates, which are indicators of enzyme activity or binding activity, in order to explore compounds that are active against drug discovery targets.

＞＞Details can be found here

　The Crystallographic Drug Discovery Platform Unit fulfills the role of a core platform for drug discovery research based on three-dimensional analysis of proteins. The unit obtains sample preparations of target proteins, crystallization and x-ray diffraction data, conducts high-throughput three-dimensional struc-tural analysis, quickly and accurately obtaining information on the three-dimensional structure of target proteins and the bonding state of candidate compounds for drugs.

＞＞Details can be found here

Crystallographic Drug Discovery Platform Unit:Structural Analysis of Targets Including Membrane Proteins and Complex Analysis of Compounds

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To support the research and development domains for implementing drug discovery and medical technology, we have established the cutting-edge training platforms and the Drug Discovery and Medical Technology Platform Units listed below. In addition to basic functions such as supporting drug discovery research, each platform unit is evolving proprietary technologies and know-how, and building technology platforms network that are unique to the Drug Discovery and Medical Technology Platforms.

Platform Unit Clusters and Cutting-Edge Training Platforms for DrugDiscovery and Medical Technology-Building a Network of Practical Technology Platforms and Promoting R&D-

NMR-based Drug Discovery Platform Unit:Systematic Analysis of the Interaction between Target Proteins and Compounds

　At the NMR-based Drug Discovery Platform Unit, we have installed approximately 40 sophisticated NMR devices, which carry out analysis of the three-dimensional structures and functions of proteins (900 MHz: 3 units, 80 MHz: 14 units, 700 MHz: 6 units, 600 MHz: 17 units), and possess technology capable of determining the three-dimensional structure of at least 300 proteins every year. The unit systematizes interactive analysis of target proteins and compounds on the basis of technology capable of measuring signals from protein with a molecular weight of 40-50,000 up to signals from compounds with a molecular weight of 100,000. A special feature of interactive analysis using NMR is the ability to capture the dynamic structural changes when proteins and compounds bind, and the attendant location information. In addition, by combining with the pipeline for NMR three-dimensional structural analysis, we are building a powerful NMR platform unit ranging from protein discovery and adjustment to analysis.

＞＞Details can be found here

Drug Discovery Chemistry Platform:Optimizing Compounds through Medicinal Chemistry

　The Drug Discovery Chemistry Platform aims to move to the next stage of research and development based on medicinal chemistry. Specifically, the unit aims to identify candidate compounds for develop-ment by promoting the synthesis of new pharmaceutical candidate compounds having pharmacological activity toward the target, and structure activity-related research based on pharmacological and drug metabolizing/pharmacokinetic assay data. By developing Fragment-Based Drug Discovery (FBDD) as a method for discovering seeds and lead compounds in the initial stages of explorative research of promis-ing pharmaceutical compounds, the platform also aims to identify new drug discovery seeds and lead compounds through collaboration with the drug discovery platform.

＞＞Details can be found here

Drug Discovery Imaging Platform Unit:Innovating the Drug Discovery Process by Introducing Molecular Imaging Technologies

　At the Drug Discovery Imaging Platform Unit, we are advancing in vivo pharmacokinetic research of marmosets (monkeys), mice and humans by utilizing molecular imaging technology focused on positron emission tomography (PET). Labeling technologies for molecular imaging probes guarantee in vivo obser-vation time and improve tracing after metabolic breakdown. Also, with a view to clinical studies of micro-doses, we aim to build new drug discovery processes, developing labeling and probes for drug candidate compounds, as well as utilizing mice-to-human streamlined molecular imaging techniques.

＞＞Details can be found here

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Disease Mouse Unit:Aiming for Further Research Application of Human Disease Model Mice

　Using ENU technologies, the Disease Mouse Unit creates over 40 types of human-disease model mice, including osteoarthritis (OA) model mice, internally and externally to RIKEN. The Unit also has a technol-ogy platform for undertaking high-throughput phenotype analysis implementing more than 100 test items for mouse phenotype analysis, and undertakes analyses of disease model mice including drug efficacy testing and hematological testing. The Unit has also built a public database of human disease model mice that contains all information regarding human disease model mice and phenotype analysis.

＞＞Details can be found here

Cellular Imaging Platform:Analyzing Real Time Biological Information with Proprietary Fluorescent Protein Technology

　At the Cellular Imaging Platform, we analyze intracellular distribution and behavior (temporal/ spatial control) in the important biomolecules controlling vital phenomena, such as propagation and differentia-tion, through cellular imaging by labeling the targeted biomolecules with fluorescence, which emits light, and tracking their movements. By using several fluorescent proteins, it is also possible to simultaneously observe the behavior of important biomolecules (multi-color imaging) in complex systems such as cell cycle analysis or intracellular signaling. Analysis of real-time changes in target proteins and intracellular information in response to pharmaceuticals is expected to be useful for drug discovery research.

＞＞Details can be found here

Leading Computational Science Unit:Using Supercomputers for Advanced In Silico Screening Technologies Including Molecular Behavior

　This unit aims for "the establishment and application of in silico drug discovery by means of leading computational technologies using large-scale, high-speed supercomputers" in order to promote drug discovery research. We implement simulation technologies to predict high-precision binding affinity, taking into account the dynamics of the complex structures of protein/low molecular compounds in aqueous solution in order to develop a high level of precision for in silico drug discovery. This is useful for deepening understanding and investigations at the molecular level of drug candidate compounds, and for specifying structural formula for promising compounds (production and selection).

＞＞Details can be found here

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Cutting-Edge Training Platforms to Improve Development Support for DrugDiscovery and Medical Technologies-Toward Innovation in Research and Development through New Technologies-

Next Generation Sequence Unit:Evaluating Target and Candidate Compounds by means of Analytical Technology for ComprehensiveGenome Dynamics

　At the Drug Discovery Imaging Platform Unit, we are advancing in vivo pharmacokinetic research of marmosets (monkeys), mice and humans by utilizing molecular imaging technology focused on positron emission tomography (PET). Labeling technologies for molecular imaging probes guarantee in vivo obser-vation time and improve tracing after metabolic breakdown. Also, with a view to clinical studies of micro-doses, we aim to build new drug discovery processes, developing labeling and probes for drug candidate compounds, as well as utilizing mice-to-human streamlined molecular imaging techniques.

＞＞Details can be found here