A5054336320- Computational Drug Discovery Methods
- Monoclonal and Polyclonal Antibodies Research
- SARS-CoV-2 and COVID-19 Research
- Protein Structure and Dynamics
- Trypanosoma species research and implications
- Carbohydrate Chemistry and Synthesis
- Cancer, Lipids, and Metabolism
- Retinoids in leukemia and cellular processes
- Chemical Synthesis and Analysis
- Advanced Breast Cancer Therapies
- Machine Learning in Materials Science
- Cancer therapeutics and mechanisms
- RNA and protein synthesis mechanisms
- Cancer-related gene regulation
- Epigenetics and DNA Methylation
- Biochemical and Molecular Research
- Bioactive Compounds and Antitumor Agents
- Pharmacogenetics and Drug Metabolism
- Enzyme Structure and Function
- Synthesis and Reactions of Organic Compounds
- Synthesis and biological activity
- RNA modifications and cancer
- Wnt/β-catenin signaling in development and cancer
- Metabolomics and Mass Spectrometry Studies
- Enzyme function and inhibition
RIKEN Center for Biosystems Dynamics Research
2018-2025
RIKEN Center for Computational Science
2025
RIKEN Center for Integrative Medical Sciences
2019-2025
RIKEN
2012-2023
Systems Biology Institute
2009-2020
Kyoto University
2020
Tokyo Institute of Technology
2000-2019
CLS Technology (Norway)
2017
Federal Research and Clinical Center of Physical-Chemical Medicine named after Y.M. Lopukhin
2017
The University of Tokyo
2008-2015
As a first step in structure-based design of highly selective and potent Cdk4 inhibitors, we performed generation novel series inhibitors. A homology model was constructed according to X-ray analysis an activated form Cdk2. Using this model, applied new de novo strategy which combined the program LEGEND with our in-house structure selection supporting system SEEDS generate scaffold candidates. In way, four classes candidates including diarylurea were identified. By constructing informer...
In addition to haem copper oxidases, all higher plants, some algae, yeasts, molds, metazoans, and pathogenic microorganisms such as Trypanosoma brucei contain an additional terminal oxidase, the cyanide-insensitive alternative oxidase (AOX). AOX is a diiron carboxylate protein that catalyzes four-electron reduction of dioxygen water by ubiquinol. T. brucei, parasite causes human African sleeping sickness, plays critical role in survival its bloodstream form. Because absent from mammals, this...
Abstract Deep learning is developing as an important technology to perform various tasks in cheminformatics. In particular, graph convolutional neural networks (GCNs) have been reported well many types of prediction related molecules. Although GCN exhibits considerable potential applications, appropriate utilization this resource for obtaining reasonable and reliable results requires thorough understanding programming. To leverage the power benefit users from chemists cheminformaticians,...
A novel in silico drug design procedure is described targeting the Main protease (Mpro) of SARS-CoV-2 virus. The combines molecular docking, dynamics (MD), and fragment orbital (FMO) calculations. binding structure properties Mpro were predicted for Nelfinavir (NFV), which had been identified as a candidate compound through repositioning, Mpro. Several poses NFV complexes generated by from four docking selected scoring with FMO energy. Then, each pose was subjected to MD simulation, 100...
Post-translational stabilization of beta-catenin through mutation the adenomatous polyposis coli (APC) gene has been proposed as an early step in colorectal carcinogenesis. Beta-catenin may translocate from cytoplasm to nucleus, where it might serve a transcriptional factor stimulate tumour formation. We investigated intracellular localization sporadic adenomas and cancers well familial (FAP). Nuclear over-expression was observed 35% (7/20) intramucosal 42% (23/55) invasive but not seen any...
Factor Xa, the converting enzyme of prothrombin to thrombin, has emerged as an alternative (to thrombin) target for drug discovery thromboembolic diseases. An inhibitor been synthesized and crystal structure complex between Des[1–44] factor Xa determined by crystallographic methods in two different forms 2.3- 2.4-Å resolution. The racemic mixture FX-2212, (2 RS )-(3′-amidino-3-biphenylyl)-5-(4-pyridylamino)pentanoic acid, inhibits activity 50% at 272 nM vitro . S -isomer FX-2212 (FX-2212a)...
In this study, we developed a new pharmacophore-based interaction fingerprint (Pharm-IF) and examined its usefulness for in silico screening using machine learning techniques such as support vector (SVM) random forest (RF) instead of similarity-based ranking. Using the docking results PKA, SRC, cathepsin K, carbonic anhydrase II, HIV-1 protease, efficiencies Pharm-IF models were compared to GLIDE score residue-based IF (PLIF) models. The combination SVM demonstrated higher enrichment factor...
A pyrrolo-pyrimidine kinase inhibitor, RK-20449, eliminates chemotherapy-resistant human primary AML stem cells in vivo.
Recent studies on the respiratory chain of Ascaris suum showed that mitochondrial NADH-fumarate reductase system composed complex I, rhodoquinone and II plays an important role in anaerobic energy metabolism adult A. suum. The is major pathway for adaptation to a hypoxic environment not only parasitic organisms, but also some types human cancer cells. Thus, enzymes are potential targets chemotherapy. We found flutolanil excellent inhibitor (IC50 = 0.058 μM) less effectively inhibits...
Dengue is a mosquito-borne viral infection that has spread globally in recent years. Around half of the world's population, especially tropics and subtropics, at risk infection. Every year, 50–100 million clinical cases are reported, more than 500,000 patients develop symptoms severe dengue infection: haemorrhagic fever shock syndrome, which threaten life Asia Latin America. No antiviral drug for available. The virus (DENV) non-structural protein 5 (NS5), possesses RNA-dependent RNA...
Abstract Assessing the hERG liability in early stages of drug discovery programs is important. The recent increase hERG-related information public databases enabled various successful applications machine learning techniques to predict inhibition. However, most these researches constructed datasets from only one database, limiting predictability and scope models. In this study, a classification model was using largest dataset for inhibition built by integrating multiple databases. integrated...
We developed the world's first web-based public database for storage, management, and sharing of fragment molecular orbital (FMO) calculation data sets describing complex interactions between biomacromolecules, named FMO Database (https://drugdesign.riken.jp/FMODB/). Each entry in contains relevant background information on how was compiled as well total energy each system interfragment interaction (IFIE) pair decomposition analysis (PIEDA) values. Currently, more than 13 600 sets, a...
Quantum chemical calculations investigated molecular recognition of SARS-CoV-2 spike glycoproteins including its N501Y variant for ACE2 and antibody. Hot spot epitope analyses revealed key residues to design drugs antibodies against COVID-19.
Abstract Several basic leucine zipper (bZIP) transcription factors have accessory motifs in their DNA-binding domains, such as the CNC motif of family or EHR small Maf (sMaf) proteins. proteins heterodimerize with sMaf to recognize CNC–sMaf binding DNA elements (CsMBEs) competition homodimers, but functional role remains elusive. In this study, we report crystal structures Nrf2/NFE2L2, a protein regulating anti-stress transcriptional responses, complex MafG and CsMBE. The restricts...
Abstract Background Mosquito control is a crucial global issue for protecting the human community from mosquito-borne diseases. There an urgent need development of selective and safe reagents mosquito control. Flavonoids, group chemical substances with variable phenolic structures, such as daidzein, have been suggested potential larvicides less risk to environment. However, mode larvicidal action flavonoids has not elucidated. Results Here, we report that several flavonoids, including...
Identification of structurally novel inhibitors lysine methyltransferase G9a has been a subject intense research in cancer epigenetics. Starting with the high-throughput screening (HTS) hit rac-10a obtained from chemical library University Tokyo Drug Discovery Initiative, structure–activity relationship unique substrate-competitive was established help X-ray crystallography and fragment molecular orbital (FMO) calculations for ligand–protein interaction. Further optimization vitro...
Identification of a selective inhibitor for particular protein kinase without inhibition other kinases is critical use as biological tool or drug. However, this very difficult because there are hundreds homologous and their domains including the ATP binding pocket have common folding pattern. To address issue, we applied following structure-based approach designing Cdk4 inhibitors: (1) identification specifically altered amino acid residues around in by comparison 390 representative kinases,...
Genetic alteration of one or more components the p16INK4A-CDK4,6/cyclin D-retinoblastoma pathway is found in than half all human cancers. Therefore, CDK4 an attractive target for development a novel anticancer agent. However, it difficult to make CDK4-specific inhibitors that do not possess activity other kinases, especially CDK2, because CDK family has high structural homology. The three-dimensional structure particularly bound with inhibitor, provided useful information synthesis...
Oncogenic Ras plays a key role in cancer initiation but also contributes to malignant phenotypes by stimulating nutrient uptake and promoting invasive migration. Because these latter cellular responses require Rac-mediated remodeling of the actin cytoskeleton, we hypothesized that molecules involved Rac activation may be valuable targets for therapy. We report genetic inactivation Rac-specific guanine nucleotide exchange factor DOCK1 ablates both macropinocytosis-dependent invasion...