Review
Pharmacology & Pharmacy
Md. Moinul, Samima Khatun, Sk. Abdul Amin, Tarun Jha, Shovanlal Gayen
Summary: This review discusses the application of fragment-based drug design in cancer treatment, as well as the design strategies for different targets, providing insights for finding suitable lead compounds through fragment-based design in high throughput screening.
BIOCHEMICAL PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Ying Yu, Junsong Guo, Zhengjun Cai, Yingchen Ju, Jun Xu, Qiong Gu, Huihao Zhou
Summary: This study utilized fragment screening and X-ray crystallography to identify new building blocks and binding mechanisms for the discovery of new GyrB inhibitors. Some chemical fragments were found to affect enzyme activity, providing new insights for the design of GyrB inhibitors.
BIOORGANIC CHEMISTRY
(2021)
Article
Pharmacology & Pharmacy
Men Thi Hoai Duong, Hee-Chul Ahn
Summary: This study utilized virtual fragment screening, STD NMR, in vitro kinase assay, and X-ray crystallography to identify 27 initial hits targeting JNK3 and demonstrating activity inhibition. The structures of JNK3 with a fragment and a potent inhibitor were determined by X-ray crystallography, revealing a common JNK3-binding feature.
Article
Materials Science, Multidisciplinary
Quinton C. Johnson, Peter Kenesei, Steve Petruzza, Jayden Plumb, Hemant Sharma, Jun -Sang Park, Elliott Marsden, Kristoffer Matheson, Michael W. Czabaj, Ashley D. Spear
Summary: This study maps and tracks the three-dimensional (3D) grain and precipitate structures of open-cell aluminum foam using advanced microstructural characterization techniques. It establishes a new scanning strategy and reconstruction algorithm to characterize a wider foam volume and develops a novel grain tracking procedure. The ability to track grains and precipitate structures throughout large deformation enables new possibilities for validating numerical models and investigating failure mechanisms.
MATERIALS CHARACTERIZATION
(2023)
Article
Biochemistry & Molecular Biology
Davide Capelli, Giulia Cazzaniga, Matteo Mori, Antonio Laghezza, Fulvio Loiodice, Martina Quaglia, Elisa Negro, Fiorella Meneghetti, Stefania Villa, Roberta Montanari
Summary: PPAR gamma is a key target for the treatment of type 2 diabetes and metabolic syndrome. To avoid adverse effects, a new opportunity is the development of molecules that inhibit PPAR gamma phosphorylation by CDK5. The study reports the identification of new PPAR gamma binders that exhibit a non-agonist profile and prevent PPAR gamma phosphorylation by stabilizing the protein and weakly inhibiting CDK5.
Article
Automation & Control Systems
Bo Chen, Kang Xu, Yongxin Zhu, Li Tian, Victor Chang
Summary: In this article, a physics law-informed federated learning method is proposed to improve the screening of synchrotron X-ray microdiffraction images while protecting data privacy.
IEEE TRANSACTIONS ON INDUSTRIAL INFORMATICS
(2023)
Review
Metallurgy & Metallurgical Engineering
Youhong Peng, Kesong Miao, Wei Sun, Chenglu Liu, Hao Wu, Lin Geng, Guohua Fan
Summary: Characterizing the microstructure and deformation mechanism of metallic materials is crucial for understanding the microstructure-property relationship. Advanced synchrotron radiation facilities have enabled non-destructive visualization of full-field structural information in three dimensions, contributing to significant progress in recent decades. Future innovations in next-generation synchrotron radiation and emerging technologies hold great potential for further advancements in material characterization.
ACTA METALLURGICA SINICA-ENGLISH LETTERS
(2022)
Article
Chemistry, Medicinal
Martyn Frederickson, Irwin R. Selvam, Dimitrios Evangelopoulos, Kirsty J. McLean, Mona M. Katariya, Richard B. Tunnicliffe, Bethany Campbell, Madeline E. Kavanagh, Sitthivut Charoensutthivarakul, Richard T. Blankley, Colin W. Levy, Luiz Pedro S. de Carvalho, David Leys, Andrew W. Munro, Anthony G. Coyne, Chris Abell
Summary: A novel strategy combining X-ray crystallographic screening with phenotypic screening is described for hit generation against promising tuberculosis (TB) targets. This method provides validation of target engagement and determination of in vitro activity. The utility of this approach is demonstrated through the screening against CYP121A1, a validated drug discovery target for TB. Several compounds showed promising activity against Mycobacterium tuberculosis strain H37Rv, and structure-based design resulted in analogues with pan-assay activity. This study highlights the importance of developing new drugs for combating drug resistance in TB.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Annarita Fiorillo, Gianni Colotti, Cecile Exertier, Anastasia Liuzzi, Francesca Seghetti, Alessandra Salerno, Jessica Caciolla, Andrea Ilari
Summary: Trypanothione reductase (TR) plays a key role in the redox homeostasis of trypanosomatid parasites and is essential for their survival in the oxidative environment. We conducted a fragment-based crystal screening and identified 12 new ligands binding to five different sites, including an allosteric pocket named the doorstop pocket, which hampers TR activity. Another site, known as the Z-site, located within the trypanothione cavity, has not yet been explored for inhibition.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Nanoscience & Nanotechnology
Sven E. Gustafson, Darren C. Pagan, Paul A. Shade, Michael D. Sangid
Summary: Elastic micromechanical fields of a nickel-based superalloy polycrystal are tracked using high energy X-ray diffraction microscopy (HEDM) to determine intragranular deformation metrics during cyclic high temperature loading. Results show that elevated temperatures lead to complex interactions among grains, with greater recovery observed at higher temperatures.
SCRIPTA MATERIALIA
(2021)
Article
Engineering, Environmental
Vijay Kumar Garg, Ankush Tanta, Arun Lal Srivastav, M. K. Tiwari, Ajay Sharma, Varinder Singh Kanwar
Summary: Pollutants released from pharmaceutical, steel, paper, and battery industries into water cause irreparable damage to the biotic system by entering the natural ecosystems and human food chain. Monitoring and determining heavy metal levels in water are crucial for human beings. In this study, TXRF spectrometry technique was used to assess the contaminant levels in water samples from an industrial area. The elemental concentrations were compared to the guidelines from WHO and BIS, and water quality parameters were assessed. The results showed that some water samples were unfit for drinking with high levels of lead and other heavy metals.
WATER ENVIRONMENT RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Satomi Kori, Yuki Shibahashi, Toru Ekimoto, Atsuya Nishiyama, Sae Yoshimi, Kosuke Yamaguchi, Satoru Nagatoishi, Masateru Ohta, Kouhei Tsumoto, Makoto Nakanishi, Pierre-Antoine Defossez, Mitsunori Ikeguchi, Kyohei Arita
Summary: Accumulation of epigenetic alterations is a major cause of tumorigenesis, with drugs targeting DNA methylation-regulating factors showing potential for cancer therapy. UHRF1, essential for DNA methylation maintenance, is overexpressed in cancer cells, making it a promising therapeutic target. The discovery of 5A-DMP as a novel TTD-binding compound and inhibitor of full-length UHRF1:LIG1 interaction suggests potential for future cancer therapy experiments.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Review
Chemistry, Multidisciplinary
Akio Yoneyama, Daiko Takamatsu, Thet-Thet Lwin, Shigehito Yamada, Tetsuya Takakuwa, Kazuyuki Hyodo, Keiichi Hirano, Satoshi Takeya
Summary: Crystal-based X-ray interferometry (CXI) detects X-ray phase shifts with the highest sensitivity among the X-ray phase-detecting methods. Phase-contrast X-ray imaging (PCXI) using CXI has the highest density resolution and has been widely applied in various fields. Novel imaging methods have also been developed to take advantage of CXI's high sensitivity, such as visualization of the effective atomic number and the three-dimensional temperature. This article reviews the principles, history, and potential applications of PCXI and CXI systems.
APPLIED SCIENCES-BASEL
(2023)
Article
Biochemistry & Molecular Biology
Erik R. Farquhar, Kanchustambham Vijayalakshmi, Rohit Jain, Benlian Wang, Janna Kiselar, Mark R. Chance
Summary: Hydroxyl radical protein footprinting is a method to assess protein structure in the solution state using synchrotron radiation. It involves generating hydroxyl radicals through X-ray radiolysis of water, which react with protein side chains and can be detected using mass spectrometry. The optimization of hydroxyl radical dose is typically done using a fluorescence assay, but a direct evaluation of labeling using intact mass spectrometry can provide more accurate and immediate feedback. This method allows for absolute and direct dosimetry for all types of protein footprinting.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Review
Chemistry, Medicinal
Qingxin Li, Congbao Kang
Summary: FBDD is a strategy used to develop potent lead molecules in drug discovery projects by identifying small-molecule fragments and growing them into molecules that bind tightly to the target. The method can be applied to multiple targets and relies on biophysical methods and careful chemical modification of fragments. NMR spectroscopy and X-ray crystallography play important roles in understanding binding modes of fragment hits and guiding fragment growth in FBDD.
CURRENT TOPICS IN MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Kate L. Wegener, Amy E. McGrath, Nicholas E. Dixon, Aaron J. Oakley, Denis B. Scanlon, Andrew D. Abell, John B. Bruning
CHEMISTRY-A EUROPEAN JOURNAL
(2018)
Article
Chemistry, Medicinal
Yiyue Xie, Jayme L. Dahlin, Aaron J. Oakley, Marco G. Casarotto, Philip G. Board, Jonathan B. Baell
JOURNAL OF MEDICINAL CHEMISTRY
(2018)
Article
Biochemistry & Molecular Biology
Claudia S. Kielkopf, Jason K. K. Low, Yee-Foong Mok, Surabhi Bhatia, Tony Palasovski, Aaron J. Oakley, Andrew E. Whitten, Brett Garner, Simon H. J. Brown
JOURNAL OF STRUCTURAL BIOLOGY
(2018)
Correction
Biochemistry & Molecular Biology
Amy E. McGrath, Alexander P. Martyn, Louise R. Whittell, Fay E. Dawes, Nehad S. El Salamouni, Jennifer L. Beck, Nicholas E. Dixon, Michael J. Kelso, Aaron J. Oakley
JOURNAL OF STRUCTURAL BIOLOGY
(2019)
Review
Biochemistry & Molecular Biology
Aaron J. Oakley
Article
Chemistry, Multidisciplinary
Thomas M. Griffiths, Aaron J. Oakley, Haibo Yu
JOURNAL OF COMPUTATIONAL CHEMISTRY
(2020)
Article
Multidisciplinary Sciences
Timothy P. Newing, Aaron J. Oakley, Michael Miller, Catherine J. Dawson, Simon H. J. Brown, James C. Bouwer, Gokhan Tolun, Peter J. Lewis
NATURE COMMUNICATIONS
(2020)
Review
Biochemistry & Molecular Biology
Michael Miller, Aaron J. Oakley, Peter J. Lewis
Summary: This review summarizes recent reports on the high-resolution structure of RNAP from the model low G + C representative Bacillus subtilis and outlines approaches for the development of antimicrobials to target RNAP from this group.
TRANSCRIPTION-AUSTIN
(2021)
Article
Biochemistry & Molecular Biology
Aaron J. Oakley
Summary: The study investigated the role of human omega-class glutathione transferases in arsenic elimination, revealing putative mono-methylarsonate binding sites through molecular dynamics simulations and proposing a reaction mechanism based on biochemical data. Insights were further gained through comparison with homologs from various animal species.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Microbiology
Joachim S. Larsen, Michael Miller, Aaron J. Oakley, Nicholas E. Dixon, Peter J. Lewis
Summary: Efficient transcription control is crucial in all organisms. HelD proteins, a new class of transcription factors, play a significant role in genome maintenance and antibiotic resistance, and are widely conserved in bacteria. Interestingly, some bacterial classes have inherited HelD genes through horizontal gene transfer, and many organisms exhibit multiple expressed isoforms of HelD, some of which are linked to antibiotic resistance.
Article
Biochemistry & Molecular Biology
Bishnu P. Paudel, Zhi-Qiang Xu, Slobodan Jergic, Aaron J. Oakley, Nischal Sharma, Simon H. J. Brown, James C. Bouwer, Peter J. Lewis, Nicholas E. Dixon, Antoine M. van Oijen, Harshad Ghodke
Summary: Elongation by RNA polymerase can be dynamically modulated by accessory factors, and the transcription-repair coupling factor TRCF can choose to either rescue or terminate the paused/stalled RNAPs. The mechanism for TRCF's choice remains unclear. Using single-molecule assays with Escherichia coli as a model, it was found that nucleotide-bound Mfd, a bacterial TRCF, can convert the elongation complex (EC) into a catalytically poised state, allowing the EC to restart transcription. After a prolonged residence in this state, ATP hydrolysis by Mfd leads to a remodeling of the EC and loss of the RNA transcript. Biophysical studies also revealed that the motor domain of Mfd can bind and partially melt DNA with a template strand overhang.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Dmitry Shishmarev, Emily Rowland, Shouvik Aditya, Srinivasan Sundararaj, Aaron J. Oakley, Angela F. Dulhunty, Marco G. Casarotto
Summary: Excitation-contraction coupling is the process by which an electrical signal is converted into muscle contraction. In this study, the interaction between two calcium channels, dihydropyridine receptor (DHPR) and ryanodine receptor 1 (RyR1), during the excitation-contraction coupling process was investigated. The results showed that the protein STAC3 interacts with a subunit of the DHPR known as the II-III loop, and this interaction differs from the interaction with the neuronal isoform STAC2. These findings provide insights into the molecular mechanism of excitation-contraction coupling in skeletal muscle.
Article
Biochemistry & Molecular Biology
Zhixue Wang, Leiyun Yang, Georg Jander, Ruchika Bhawal, Sheng Zhang, Zhenhua Liu, Aaron Oakley, Jian Hua
Summary: AVRRPT2-INDUCED GENE2A (AIG2A) and AIG2B prevent tryptophan-derived secondary metabolites from activating salicylic acid-mediated defense and balance chemical defense systems.
Article
Biochemistry & Molecular Biology
Aaron J. Oakley
Summary: With the development of accurate protein structure prediction algorithms, artificial intelligence (AI) has become a powerful tool in structural biology. By analyzing large amounts of protein sequence data, AI algorithms can complement experimental structure data found in databases. In this study, the EBI AlphaFold Protein Structure Database was used to analyze human proteins containing the cytosolic glutathione transferase (cGST) fold. A total of 39 proteins were discovered, exhibiting various functions such as enzymes, chloride ion channels, and protein-protein interaction mediators. The AI-based structure prediction algorithm AlphaFold-multimer was used to predict structures of the cGST domains and their potential homo- and heterodimers.
Article
Infectious Diseases
Zorik Chilingaryan, Stephen J. Headey, Allen T. Y. Lo, Zhi-Qiang Xu, Gottfried Otting, Nicholas E. Dixon, Martin J. Scanlon, Aaron J. Oakley