Article
Biochemistry & Molecular Biology
Hye Ree Yoon, Gyoung Jin Park, Anand Balupuri, Nam Sook Kang
Summary: Fragment-based drug discovery (FBDD) is an effective method for generating diverse and novel drug candidates. This study introduces a novel screening method, TWN-FS, based on topological water networks (TWNs), which provides valuable insights into fragment localization and shape within protein binding sites.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2023)
Review
Chemistry, Medicinal
Kirsten McAulay, Alan Bilsland, Marta Bon
Summary: Fragment-based drug discovery plays a crucial role in identifying new ligands, and there is increasing interest in targeted covalent inhibitors. Covalent fragment-based approaches have led to the discovery of novel targets and binding sites, including previously considered "undruggable" targets. Understanding the properties and reactivity of these covalent fragments is important in drug discovery.
Review
Biochemistry & Molecular Biology
Wenchao Lu, Milka Kostic, Tinghu Zhang, Jianwei Che, Matthew P. Patricelli, Lyn H. Jones, Edward T. Chouchani, Nathanael S. Gray
Summary: Targeted covalent inhibitors have become a focus in drug discovery, with chemoproteomic strategies and fragment-based drug discovery leading to the identification of new drugs and protein targets. This approach enables high-throughput discovery of potential protein targets and allows for targeting of various amino acids using new chemical technologies.
RSC CHEMICAL BIOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Namdev S. Togre, Ana M. Vargas, Gunapati Bhargavi, Mohan Krishna Mallakuntla, Sangeeta Tiwari
Summary: The emergence of drug-resistant mycobacteria is a global threat that requires the development of new potent anti-mycobacterial drugs. Fragment-based drug discovery (FBDD) has been recognized as a popular approach to identify potent fragment molecules using virtual, computational, and biophysical methods. FBDD overcomes the limitations of traditional methods and is important for combating NTM and Mtb infections.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Yaqian Liu, Ruoxing Jin, Hui Lu, Kangjie Bian, Rui Wang, Lei Wang, Rui Gao, Jiahai Zhang, Jihui Wu, Xuebiao Yao, Xing Liu, Dan Liu, Xisheng Wang, Zhiyong Zhang, Ke Ruan
Summary: YEATS family proteins recognize acylated histones and regulate chromatin structure, gene transcription, and stress signaling. In this study, researchers identified inhibitors for the AF9 YEATS domain and designed new inhibitors based on complex structures and affinity assays. These inhibitors showed antiproliferation activities in AF9-sensitive cancer cells. This work provides a basis for further optimization of AF9 YEATS inhibitors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Roberto Leon, Jorge Soto-Delgado, Elizabeth Montero, Matias Vargas
Summary: The study utilizes a fragment-based drug design strategy and heuristic search algorithm to design new inhibitors by deconstructing known ligands and reassembling fragments to generate new ligands. Evaluation of the approaches involves comparing the binding energy of the new ligands with the known ligands.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Chemistry, Medicinal
Mohan Krishna Mallakuntla, Namdev S. Togre, Destiny B. Santos, Sangeeta Tiwari
Summary: Tuberculosis (TB) and HIV continue to be global health problems, demanding the development of new drugs for their treatment. Traditional approaches have limitations in producing diverse drugs, necessitating the use of new technologies. Fragment-based drug discovery has proven successful in developing potent inhibitors for various targets.
Review
Biochemistry & Molecular Biology
Cassandra Kennedy, Katherine McPhie, Katrin Rittinger
Summary: The ubiquitin system offers a wealth of potential drug targets, but there is a lack of effective inhibitors for the proteins within this system. Fragment-based drug discovery (FBDD) provides a screening platform that combines structural biology and proteomics to discover inhibitors within the ubiquitin system. This mini review summarizes the current scope and new frontiers of FBDD in relation to ubiquitin-activating, ubiquitin-conjugating, ubiquitin ligase, and deubiquitinating enzymes.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Review
Chemistry, Medicinal
Kasper P. Lundquist, Vipul Panchal, Charlotte H. Gotfredsen, Ruth Brenk, Mads H. Clausen
Summary: The rapid development in fragment-based drug discovery and medicinal targeting of RNA has opened up possibilities for combining technologies and methods in novel ways. This review discusses the use of fragment-based screening against RNA targets, including the latest screening and hit validation methods, and provides insights on future perspectives in this field.
Review
Chemistry, Medicinal
Yifan Zhao, Bo Jiang, Zhouyang Gu, Tianle Chen, Wei Yu, Shiyin Liu, Xing Liu, Dongyin Chen, Fei Li, Weilin Chen
Summary: Post-translational methylation of histone lysine or arginine residues by histone methyltransferases (HMTs) is crucial for gene regulation and physiological processes, and is implicated in human diseases. Histone methyltransferases are potential therapeutic targets and the development of inhibitors has been pursued over the past decade. Covalent inhibitors for HMTs have gained increasing attention and this review focuses on their discovery, characterization, and applications, as well as challenges and future directions in drug discovery.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Chemistry, Medicinal
Daniel Schaefer, Xinlai Cheng
Summary: Despite the increasing number of biologics license applications, the development of covalent inhibitors remains a growing field in drug discovery. The successful approval of certain covalent protein kinase inhibitors and the recent discovery of covalent inhibitors for viral proteases represent advancements in covalent drug development. Covalent bonds targeting proteins offer advantages in target selectivity, drug resistance, and administration concentration. The electrophile (warhead) is a crucial factor for covalent inhibitors, dictating selectivity and reactivity, and can be modified through rational designs. Covalent inhibitors are also finding applications in protein degradation and targeting chimeras (PROTACs) for 'undruggable' proteins, as well as in the treatment of SARS-CoV-2.
Review
Pharmacology & Pharmacy
Hanna F. Klein, David J. Hamilton, Iwan J. P. de Esch, Maikel Wijtmans, Peter O'Brien
Summary: This review discusses the synthetic strategies for preparing 3D fragments based on 25 papers published from 2011 to mid-May 2020, emphasizing diversity-oriented synthesis, scaffold synthesis and diversification, as well as computational design and synthesis. The conclusion suggests that a workflow combining computational design and other strategies, along with considerations of fragment properties and 3D shape, could promote the wider use of 3D fragments in fragment libraries and facilitate fragment-to-lead optimization.
DRUG DISCOVERY TODAY
(2022)
Article
Chemistry, Multidisciplinary
Yaniv Tivon, Gianna Falcone, Alexander Deiters
Summary: This new approach selectively modifies native proteins in their biological environment using electrophilic covalent aptamers, providing high target specificity and broad programmability. Covalent aptamers address issues such as instability and offer advantages in protein modification and detection, as well as nuclease-resistant enzyme inhibition.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Biochemistry & Molecular Biology
Angela Eden, Jing Zhao, Yuanyuan Xiao, James Gibson, Chunyu Wang
Summary: Alzheimer's disease is a serious public health crisis with limited treatment options. The inhibition of gamma-secretase has been a leading approach in drug discovery for Alzheimer's disease, but previous inhibitors have failed in clinical trials due to side effects. This study introduces a novel approach by discovering a substance called 6H8 that can covalently bind and inhibit the active subunit of gamma-secretase. This finding opens up new possibilities for drug development in Alzheimer's disease.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Ling Fu, Youngeun Jung, Caiping Tian, Renan B. Ferreira, Ruifeng Cheng, Fuchu He, Jing Yang, Kate S. Carroll
Summary: We developed an effective strategy for selective bioconjugation using the 'polarity reversal' of sulfur when cysteine is oxidized to sulfenic acid. A global map of a human sulfenome susceptible to covalent modification was presented. Our findings demonstrate the vast presence of ligandable sulfenic acids in the human proteome and highlight the utility of nucleophilic small molecules in the fragment-based covalent ligand discovery pipeline.
NATURE CHEMICAL BIOLOGY
(2023)
Review
Cell Biology
Joe G. Greener, Shaun M. Kandathil, Lewis Moffat, David T. Jones
Summary: This passage discusses the application of machine learning in the analysis of biological data and provides guidance for experimentalists. The increasing scale and complexity of biological data have led to a growing use of machine learning in biology.
NATURE REVIEWS MOLECULAR CELL BIOLOGY
(2022)
Article
Pharmacology & Pharmacy
Bo Qin, Gregory B. Craven, Pengjiao Hou, Julian Chesti, Xinran Lu, Emma S. Child, Rhodri M. L. Morgan, Wenchao Niu, Lina Zhao, Alan Armstrong, David J. Mann, Sheng Cui
Summary: This study successfully applied quantitative irreversible tethering (qIT) to identify fragments that can inhibit the proteases of Enterovirus 71 and SARS-CoV-2, and found that the inhibition could disrupt the active dimeric unit.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Engineering, Chemical
Lingfeng Gui, Claire S. Adjiman, Amparo Galindo, Fareed Bhasha Sayyed, Stanley P. Kolis, Alan Armstrong
Summary: The combination of chloroformamidinium and diisopropylcarbodiimide has been widely used for amino acid activation, but it can generate unwanted hydrogen cyanide at 20 degrees C, which raises safety concerns. In this study, a computational investigation was conducted to understand the mechanism and kinetics of hydrogen cyanide formation, providing a theoretical basis for developing strategies to suppress its generation.
INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH
(2023)
Article
Chemistry, Organic
Zhenhao Zhong, Julian Chesti, Alan Armstrong, James A. Bull
Summary: Sulfoximines offer a new approach for improving medicinal chemistry with the addition of other functional groups in sulfonyl compounds. By optimizing conditions, successful synthesis of carbamates with previously low yields, especially those containing pi-functionality, was achieved, including the preparation of propargyl sulfoximine carbamates as potential click handles. Notably, using Rh-2 (esp)(2) as catalyst and a DOE optimization approach led to significantly increased yields.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Roman O. O. Fedoryshchak, Andrii Gorelik, Mengjie Shen, Maria M. M. Shchepinova, Inmaculada Perez-Dorado, Edward W. W. Tate
Summary: Protein-protein interactions (PPIs) play important roles in biology. However, there are limited methods to study interactions driven by specific post-translational modifications (PTMs). In this study, a panel of novel myristic acid analog probes were designed and synthesized to capture PTM-specific interactions. These probes successfully labeled NMT substrates in cells and formed covalent crosslinks with their interacting proteins, allowing the identification of known and novel interactors of myristoylated proteins.
Article
Microbiology
Elizabeth V. K. Ledger, Katie Lau, Edward W. Tate, Andrew M. Edwards
Summary: Pathogenic bacteria need to repair DNA damage from antibiotics and the immune system to survive in the host environment. The SOS response is a vital pathway for bacterial DNA repair and could be targeted for new therapeutics to sensitize bacteria to antibiotics and the immune response. Through a mutant screen, 16 genes potentially involved in the SOS response were identified in Staphylococcus aureus, with 3 genes affecting susceptibility to ciprofloxacin. The loss of the tyrosine recombinase XerC also increased susceptibility to antibiotics and host immune defenses, suggesting that inhibiting XerC could sensitize S. aureus to both antibiotics and the immune response.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2023)
Article
Biochemistry & Molecular Biology
Shahid Rehan, Dale Tranter, Phillip P. P. Sharp, Gregory B. B. Craven, Eric Lowe, Janet L. L. Anderl, Tony Muchamuel, Vahid Abrishami, Suvi Kuivanen, Nicole A. A. Wenzell, Andy Jennings, Chakrapani Kalyanaraman, Tomas Strandin, Matti Javanainen, Olli Vapalahti, Matthew P. P. Jacobson, Dustin McMinn, Christopher J. J. Kirk, Juha T. Huiskonen, Jack Taunton, Ville O. O. Paavilainen
Summary: This study describes a cyclic depsipeptide called KZR-8445 that selectively disrupts the biogenesis of secretory and membrane proteins in a signal peptide-dependent manner by targeting the Sec61 translocon. KZR-8445 effectively inhibits the secretion of pro-inflammatory cytokines in immune cells and demonstrates therapeutic efficacy in a mouse model of rheumatoid arthritis. The binding of KZR-8445 stabilizes the lateral gate helices of Sec61, preventing the movement of select signal peptides into the lipid bilayer and providing a framework for the discovery of novel therapeutics that modulate Sec61-mediated protein biogenesis in a targeted manner.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Luke A. Yates, Elias A. Tannous, R. Marc Morgan, Peter M. Burgers, Xiaodong Zhang
Summary: This study reveals the phosphorylation circuit that regulates checkpoint recruitment and function in response to DNA damage. The interaction between Ddc2 and RPA modulates the association between RPA and ssDNA, and phosphorylated Ddc2 enhances its recruitment to RPA-ssDNA, promoting DNA damage checkpoint signaling.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Emma C. Couves, Scott Gardner, Tomas B. Voisin, Jasmine K. Bickel, Phillip J. Stansfeld, Edward W. Tate, Doryen Bubeck
Summary: This study reveals the role of CD59 in immune regulation, by preventing the formation of MAC toxins through inhibiting the binding of C8 and C9 to the membrane. CD59 also protects membrane integrity by altering the trajectory of C9 beta-hairpins, restricting MAC polymerization. These findings are significant for understanding the dual roles of CD59 in MAC and its involvement in host-pathogen interactions.
NATURE COMMUNICATIONS
(2023)
Article
Biology
Amit Kumar, Oscar Vadas, Nicolas Dos Santos Pacheco, Xu Zhang, Kin Chao, Nicolas Darvill, Helena O. Rasmussen, Yingqi Xu, Gloria Meng-Hsuan Lin, Fisentzos A. Stylianou, Jan Skov Pedersen, Sarah L. Rouse, Marc L. Morgan, Dominique Soldati-Favre, Stephen Matthews
Summary: The intracellular parasites belonging to the phylum of Apicomplexa employ substrate-dependent gliding motility to invade host cells. The glideosome-associated connector (GAC), a conserved protein, plays a crucial role in this process. The crystal structure of Toxoplasma gondii GAC reveals a unique armadillo repeat region that adopts a closed ring conformation. The properties of GAC suggest that it can adopt multiple conformations from closed to open and extended, and a multi-conformational model is proposed for its assembly and regulation within the glideosome.
Article
Computer Science, Interdisciplinary Applications
Lingfeng Gui, Yijun Yu, Titilola O. Oliyide, Eirini Siougkrou, Alan Armstrong, Amparo Galindo, Fareed Bhasha Sayyed, Stanley P. Kolis, Claire S. Adjiman
Summary: Computer-aided molecular design (CAMD) methods are used to generate promising solvents with enhanced reaction kinetics by utilizing a reliable model of solvent effects on reaction rates. In this study, a surrogate model parameterized from computer experiments, specifically quantum-mechanical (QM) data on rate constants, is employed. The selection of solvents for these computer experiments plays a crucial role due to the cost and difficulty of QM calculations. Model-based design of experiments (MBDoE) is used to identify an information-rich solvent set and incorporate it into a QM-CAMD framework. The results of three case studies demonstrate that MBDoE can yield surrogate models with good statistics and identify solvents with enhanced predicted performance in a few iterations and at low computational cost.
COMPUTERS & CHEMICAL ENGINEERING
(2023)
Article
Chemistry, Multidisciplinary
Ying Chen, Gregory B. Craven, Roarke A. Kamber, Adolfo Cuesta, Serhii Zhersh, Yurii S. Moroz, Michael C. Bassik, Jack Taunton
Summary: Advances in chemoproteomic technology have allowed for the identification of covalent interactions between small molecules and protein nucleophiles. The development of a chemoproteomic platform using enantiomeric pairs of clickable arylsulfonyl fluoride probes enables the direct identification of electrophile sites. This platform has led to the discovery of ligandable tyrosines and lysines within various protein sites for the development of covalent chemical probes.
Article
Multidisciplinary Sciences
Douglas Sammon, Anja Krueger, Marta Busse-Wicher, Rhodri Marc Morgan, Stuart M. Haslam, Benjamin Schumann, David C. Briggs, Erhard Hohenester
Summary: Heparan sulfate (HS) and chondroitin sulfate (CS) control development and physiology in a specific manner. The modification of core proteins with HS or CS is carried out selectively by N-acetylglucosaminyltransferase EXTL3 and equally by N-acetylgalactosaminyltransferase CSGALNACT2, respectively. Phosphorylation accelerates linker synthesis and the initiation of HS and CS.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Matthew E. H. White, Jesus Gil, Edward W. Tate
Summary: Covalent drug discovery has experienced a resurgence and reactive cysteine profiling has emerged as a platform for ligand discovery. However, the scope of this approach at the whole-proteome level has not been fully explored. By combining AlphaFold2-predicted side-chain accessibilities and a meta-analysis of cysteine profiling datasets, accessibility biases in cysteines were revealed. Analysis of cysteine-fragment interactions showed increased bias against buried cysteine residues. Future directions for increasing coverage were proposed.
CELL CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Mostafa Jamshidiha, Thomas Lanyon-Hogg, Charlotte L. Sutherell, Gregory B. Craven, Montse Tersa, Elena De Vita, Delia Brustur, Inmaculada Perez-Dorado, Sarah Hassan, Rita Petracca, Rhodri M. Morgan, Maximo Sanz-Hernandez, Jim C. Norman, Alan Armstrong, David J. Mann, Ernesto Cota, Edward W. Tate
Summary: Rab27A, a small GTPase, plays a significant role in promoting the growth and invasion of multiple cancer types by enhancing secretion of chemokines, metalloproteases, and exosomes. Its flat topology and high affinity for GTP make it a challenging target for inhibition by small molecules. By utilizing unique cysteine residues, covalent ligands for native Rab27A have been identified, providing a platform for developing competitive inhibitors of the Rab27A-effector interaction interface.
RSC MEDICINAL CHEMISTRY
(2022)
