Article
Biochemistry & Molecular Biology
Yuki Bessho, Tatsuo Akaki, Yoshinori Hara, Maki Yamakawa, Shingo Obika, Genki Mori, Minoru Ubukata, Katsutaka Yasue, Yoshitomi Nakane, Yasuo Terasako, Takuya Orita, Satoki Doi, Tomoko Iwanaga, Ayumi Fujishima, Tsuyoshi Adachi, Hiroshi Ueno, Takahisa Motomura
Summary: Structure-based drug design led to the discovery of highly potent dual inhibitors of PDHK2 and PDHK4, which are fascinating drug targets for various diseases including diabetes and cancers.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Oliver Laufkoetter, Huabin Hu, Filip Miljkovic, Juergen Bajorath
Summary: Allosteric kinase inhibitors are highly selective and promising candidates for kinase drug discovery. Exploring allosteric mechanisms is of great interest in basic research and drug design. X-ray structures of kinase complexes have provided valuable data for identifying and characterizing allosteric inhibitors. This study presents a comprehensive survey of allosteric kinase inhibitors and activators based on publicly available X-ray structures, mapping their binding sites and distribution in kinase binding pockets. The structural features of these compounds are discussed, and active structural analogues and high-confidence target annotations are identified, suggesting additional activities for some allosteric inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Tatsuo Akaki, Yuki Bessho, Takashi Ito, Shingo Fujioka, Minoru Ubukata, Genki Mori, Kenji Yamanaka, Takuya Orita, Satoki Doi, Tomoko Iwanaga, Kazutaka Ikegashira, Yoshiji Hantani, Isao Nakanishi, Tsuyoshi Adachi
Summary: This study utilized a fragment-based lead discovery approach to identify inhibitors against PDHKs with novel chemotypes, providing new structural insights into the deep binding interactions at the ATP site. The research successfully generated lead compounds with high selectivity and efficiency, opening up a new direction for the development of PDHKs inhibitors.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Christian G. Kurz, Franziska Preuss, Amelie Tjaden, Martin Cusack, Jennifer Alisa Amrhein, Deep Chatterjee, Sebastian Mathea, Lena Marie Berger, Benedict-Tilman Berger, Andreas Kramer, Michael Weller, Tobias Weiss, Susanne Mueller, Stefan Knapp, Thomas Hanke
Summary: Serine/threonine kinase 17A (DRAK1) belongs to the dark kinome family and its cellular function and involvement in pathophysiological processes are not well understood. This study optimized a potential DRAK1 inhibitor CK156, which showed high potency and selectivity in vitro. However, the inhibition of cell growth in glioma cells was observed only at low micromolar concentrations.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Cell Biology
Sharzil Haris Khan, Hilal Tayara, Kil To Chong
Summary: Protein-protein interactions are essential for biological processes and can help in drug development. Computational methods that use sequential information of proteins have been proposed to predict binding sites. A neural network-based model called ProB-site uses evolutionary and structural information to generate feature sets, which are then classified.
Article
Biology
Ondrej Vaculik, Eliska Chalupova, Katarina Gresova, Tomas Majtner, Panagiotis Alexiou
Summary: RNA-binding proteins play important roles in biological processes and their dysfunction can lead to various diseases. This study addresses the limited availability of training data by utilizing transfer learning to predict RBP binding sites, and demonstrates the advantages of transfer learning.
Article
Multidisciplinary Sciences
Ritwika S. Basu, Michael B. Sherman, Matthieu G. Gagnon
Summary: During translation initiation, IF2 holds fMet-tRNA(i)(fMet) in the P site and facilitates the transition of the ribosome to the elongation phase. Our study reveals the mechanism of separation between IF2 and initiator tRNA and provides insights into the regulation of ribosome during translation elongation.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Silvia Arifi, Julian A. Marschner, Julius Pollinger, Laura Isigkeit, Pascal Heitel, Astrid Kaiser, Lennart Obeser, Georg Hoefner, Ewgenij Proschak, Stefan Knapp, Apirat Chaikuad, Jan Heering, Daniel Merk
Summary: The lipid-sensing transcription factor PPAR γ can bind to antidiabetic TZD drugs, oxidized vitamin E metabolites, and vitamin E mimetic garcinoic acid. While the effects of the second binding on PPAR γ activity are unclear, a selective ligand of the second site has been developed, revealing potential noncanonical regulation of PPAR γ activities. This alternative binding diminishes FOXO signaling and may have therapeutic applications.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Medicinal
Ying Yang, Lei Zhang, Jinying Tian, Fei Ye, Zhiyan Xiao
Summary: A hierarchical virtual screening identified four potential PTP1B inhibitors with distinct structures, among which H3 and H9 showed selectivity to PTP1B. Key residues responsible for potent allosteric inhibition and excellent PTP selectivity were identified through molecular dynamics simulations and MM-GBSA calculations, aiding future molecular design of PTP1B allosteric inhibitors.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Biochemistry & Molecular Biology
Victoria R. Mingione, Zachariah H. Foda, YiTing Paung, Hannah Philipose, Aziz M. Rangwala, Yibing Shan, Markus A. Seeliger
Summary: Allostery plays a critical role in regulating protein activity and has important implications in human disease and drug discovery. However, identifying allosteric binding sites remains challenging due to their cryptic nature and lack of clear geometric or chemical features. In this study, we present a computational protocol that utilizes unbiased ligand binding simulations to predict allosteric ligand binding sites. We demonstrate the feasibility of this protocol using Src kinase as a model system and validate a novel allosteric site using virtual screening and experimental assays. This study provides proof-of-concept for the use of unbiased ligand binding simulations in identifying cryptic allosteric binding sites.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Vitor Mendes, Simon R. Green, Joanna C. Evans, Jeannine Hess, Michal Blaszczyk, Christina Spry, Owain Bryant, James Cory-Wright, Daniel S-H Chan, Pedro H. M. Torres, Zhe Wang, Navid Nahiyaan, Sandra O'Neill, Sebastian Damerow, John Post, Tracy Bayliss, Sasha L. Lynch, Anthony G. Coyne, Peter C. Ray, Chris Abell, Kyu Y. Rhee, Helena I. M. Boshoff, Clifton E. Barry, Valerie Mizrahi, Paul G. Wyatt, Tom L. Blundell
Summary: Coenzyme A (CoA) is a crucial factor in various metabolic pathways and cellular processes, particularly in prokaryotes such as Mycobacterium tuberculosis. The biosynthesis of CoA involves five steps, with the second and third steps catalyzed by a bifunctional protein CoaBC in most prokaryotes. The researchers identified inhibitors of M. tuberculosis CoaB through a high-throughput screen and discovered a cryptic allosteric binding site within the enzyme.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Camille Henry, Neema Mbele, Michael M. Cox
Summary: In bacteria, the repair of post-replication gaps by homologous recombination requires the action of RecF, RecO and RecR proteins. However, it is still unclear how RecF targets the system to appropriate sites. The hypothesis of specific RecF binding to gap ends was tested by examining RecF and RecFR binding to more than 40 DNA substrates, but no specific DNA binding was observed. The results suggest that factors other than RecF or RecFR may be involved in targeting post-replication gaps, possibly through interactions with additional proteins.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Chemistry, Multidisciplinary
Ofentse Mafethe, Tlhalefo Ntseane, Tendamudzimu Harmfree Dongola, Addmore Shonhai, Njabulo Joyfull Gumede, Fortunate Mokoena
Summary: Plasmodium falciparum, the most lethal and widespread form of malaria, has a validated drug target called heat shock protein 90 (PfHsp90), which is essential for parasite survival. The N-terminal domain of PfHsp90 is highly conserved, making it a challenge to develop selective inhibitors. In this study, a pharmacophore model was used to discover diverse chemical scaffolds that exhibit anti-Plasmodium activities.
Review
Chemistry, Medicinal
Bharat Goel, Shivani Jaiswal, Shreyans K. K. Jain
Summary: Microtubules are important intracellular targets for anticancer activity. Various drugs, such as paclitaxel and vinblastine, act by altering the dynamics of microtubules. In this study, the potential of indole derivatives as colchicine-binding site inhibitors is reviewed. These derivatives have shown the ability to inhibit cancer cell proliferation, induce apoptosis, and disrupt microtubule formation. Understanding the structure-activity relationship of these compounds could lead to the development of novel and effective cancer therapies.
ARCHIV DER PHARMAZIE
(2023)
Article
Chemistry, Medicinal
Femke A. Meijer, Maxime C. M. van den Oetelaar, Richard G. Doveston, Ella N. R. Sampers, Luc Brunsveld
Summary: RORγt is a key positive regulator in Th17 cell differentiation and proinflammatory cytokine production, and dysregulation can lead to autoimmune diseases. Inhibition of RORγt with small molecules holds therapeutic potential, but targeting discovery of novel allosteric ligands is challenging. Introducing covalent, orthosteric chemical probes for RORγt could aid in screening for new allosteric ligands.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Ethan Ahler, Ames C. Register, Sujata Chakraborty, Linglan Fang, Emily M. Dieter, Katherine A. Sitko, Rama Subba Rao Vidadala, Bridget M. Trevillian, Martin Golkowski, Hannah Gelman, Jason J. Stephany, Alan F. Rubin, Ethan A. Merritt, Douglas M. Fowler, Dustin J. Maly
Article
Chemistry, Multidisciplinary
Linglan Fang, Sujata Chakraborty, Emily M. Dieter, Zachary E. Potter, Chloe K. Lombard, Dustin J. Maly
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2019)
Article
Biochemical Research Methods
Martin Golkowski, Venkata Narayana Vidadala, Ho-Tak Lau, Anna Shoemaker, Masami Shimizu-Albergine, Joseph Beavo, Dustin J. Maly, Shao-En Ong
JOURNAL OF PROTEOME RESEARCH
(2020)
Article
Biochemistry & Molecular Biology
Linglan Fang, Jessica Vilas-Boas, Sujata Chakraborty, Zachary E. Potter, Ames C. Register, Markus A. Seeliger, Dustin J. Maly
ACS CHEMICAL BIOLOGY
(2020)
Article
Biochemistry & Molecular Biology
Carrie S. Tambo, Sarvind Tripathi, B. Gayani K. Perera, Dustin J. Maly, Alexander J. Bridges, Gert Kiss, Seth M. Rubin
Summary: Cyclin-dependent kinases (CDKs) are crucial regulators of cell proliferation and have been studied as potential targets for cancer therapy. The interaction between CDKs and cyclins, their activators, plays a central role in cell cycle progression. In this study, a biolayer interferometry assay was used to quantify CDK-cyclin binding interactions. The results showed that Type I inhibitors increase the affinity between CDK2 and cyclin A by slowing down cyclin dissociation, while Type II inhibitors and other small-molecule CDK2 binders have different effects on cyclin association and dissociation kinetics, leading to decreased affinity. The findings suggest that the plasticity of the CDK2 active site contributes to the differential impact of small molecules on cyclin binding kinetics.
ACS CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Lu Xiao, Linglan Fang, Sayantan Chatterjee, Eric T. Kool
Summary: RNA 2'-OH acylation is widely used for structure mapping and conjugation, and depends on selective reactions with unpaired nucleotides. We prepared a range of structurally diverse acylimidazole reagents and used deep sequencing to study their reactivity and selectivity in a variety of RNA structures. Our results demonstrate that the reagent scaffold significantly affects reactivity profiles and highlight new acylating agents with altered selectivity, including compounds that show elevated selectivity within loops and reduced off-target reactivity in loop closing base pairs. We also discovered a simple reagent that is cell permeable and can map RNA structure in the presence of protein contacts, and describe reagents with elevated selectivity within small loops for site-selective labeling.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Biochemistry & Molecular Biology
Cindy T. T. Wei, Nicholas A. A. Popp, Omri Peleg, Rachel L. L. Powell, Elhanan Borenstein, Dustin J. J. Maly, Douglas M. M. Fowler
Summary: Researchers have developed a chemically activated DNA-binding Cas9 switch called ciCas9, which enables temporal control over seven Cas9 effectors including base editors and transcriptional activators. Using this switch, they analyzed the kinetics of base editing and found that editing occurs within hours and early rapid editing predicts the final editing magnitude. They also discovered that editing at preferred nucleotides increases bystander edits. The ciCas9 switch offers a versatile approach for generating chemically controlled Cas9 effectors and enables precise temporal effector control for kinetic studies.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Linglan Fang, Lu Xiao, Yong Woong Jun, Yoshiyuki Onishi, Eric T. T. Kool
Summary: The presence of a hydroxyl group at the 2'-position in ribose makes RNA susceptible to hydrolysis. In this study, reversible 2'-OH acylation was presented as a general strategy to preserve RNA stability. High-yield polyacylation of 2'-hydroxyls effectively protected RNAs from degradation, and subsequent treatment with nucleophilic reagents removed acylation adducts and recovered a wide range of RNA functions.
Article
Biochemistry & Molecular Biology
Lu Xiao, Linglan Fang, Eric T. Kool
Summary: The reactivity of RNA 2'-OH acylation has been extensively studied in this research. The results show that there is a wide range of reactivity among single-stranded RNA sequences, with nearest neighbors playing a significant role. Interestingly, certain small loops exhibit much higher reactivity compared to single-stranded RNAs, which is attributed to conformational constraints.
CELL CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Zachary E. Potter, Ho-Tak Lau, Sujata Chakraborty, Linglan Fang, Miklos Guttman, Shao-En Ong, Douglas M. Fowler, Dustin J. Maly
CELL CHEMICAL BIOLOGY
(2020)