Article
Multidisciplinary Sciences
Carmen Oi Ning Leung, Yang Yang, Rainbow Wing Hei Leung, Karl Kam Hei So, Hai Jun Guo, Martina Mang Leng Lei, Gregory Kenneth Muliawan, Yuan Gao, Qian Qian Yu, Jing Ping Yun, Stephanie Ma, Qian Zhao, Terence Kin Wah Lee
Summary: The study reveals that CDK6 plays a crucial role in lenvatinib-resistant HCC by promoting the accumulation of liver cancer stem cells and activating the Wnt/beta-catenin signaling pathway. The combination of lenvatinib and palbociclib shows synergistic effects in inhibiting lenvatinib-resistant HCC and reshaping the tumor immune microenvironment.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Chinmaya U. Joisa, Kevin A. Chen, Matthew E. Berginski, Brian T. Golitz, Madison R. Jenner, Gabriela Herrera Loeza, Jen Jen Yeh, Shawn M. Gomez
Summary: Protein kinase activity plays a central role in cellular information transfer and its dysfunction is a common driver of diseases, including cancer. The development of therapies targeting kinases has rapidly grown, making it important to understand the relationship between kinase inhibitor treatment and their effects on cellular phenotype. In this study, computational models were built using large-scale kinome profiling data sets, achieving high prediction accuracy. Well-characterized and understudied kinases that significantly affect cell responses were identified. Experimental validation was conducted, demonstrating that broad quantification of kinome inhibition state is highly predictive of downstream cellular phenotypes.
Article
Dermatology
Nozomi Jimura, Kazuyasu Fujii, Zhiwei Qiao, Ryuto Tsuchiya, Yuki Yoshimatsu, Tadashi Kondo, Takuro Kanekura
Summary: The study identified Src pathway as a potential target in combination therapy for CTCL, with Ponatinib enhancing apoptosis induced by HDACis.
JOURNAL OF DERMATOLOGICAL SCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Emilie Logie, Claudina Perez Novo, Amber Driesen, Pieter Van Vlierberghe, Wim Vanden Berghe
Summary: Protein kinases play a crucial role in transducing cellular signals and orchestrating biological processes through phosphorylation of substrate proteins. Recent studies have shown their involvement in ferroptosis, an iron-dependent cell death linked to toxic lipid peroxidation. Different kinase signaling changes are induced by apoptotic and ferroptotic cell death, indicating that kinome profiling could be a valuable approach to identify sensitization modalities of novel anti-cancer agents.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Multidisciplinary
Hirotomo Moriwaki, Shin Saito, Tomoya Matsumoto, Takayuki Serizawa, Ryo Kunimoto
Summary: In drug discovery, predicting activity and absorption, distribution, metabolism, excretion, and toxicity parameters is crucial. Recent research has focused on prediction methods using deep learning and non-deep learning approaches. This study compared and discussed the prediction results of activity using both methods on in-house assay data for hundreds of kinases. The multitask graph neural network (GNN) model outperformed the non-deep learning model and showed extrapolative validity. The findings suggest that ligand-based prediction methods can be used for activity prediction and drug design.
Article
Multidisciplinary Sciences
Corvin Walter, Adinarayana Marada, Tamara Suhm, Ralf Ernsberger, Vera Muders, Cansu Kuecuekkoese, Pablo Sanchez-Martin, Zehan Hu, Abhishek Aich, Stefan Loroch, Fiorella Andrea Solari, Daniel Poveda-Huertes, Alexandra Schwierzok, Henrike Pommerening, Stanka Matic, Jan Brix, Albert Sickmann, Claudine Kraft, Joern Dengjel, Sven Dennerlein, Tilman Brummer, F. -Nora Voegtle, Chris Meisinger
Summary: The study shows that DYRK1A phosphorylates TOM70 to promote import of precursor proteins into mitochondria. Inhibition of DYRK1A impairs mitochondrial structure and function, leading to a decrease in metabolite carrier import capacity.
NATURE COMMUNICATIONS
(2021)
Article
Biochemical Research Methods
Laura J. Marholz, Joel D. Federspiel, Hyunsuk Suh, Mireia Fernandez Ocana
Summary: This study reports the development of a targeted mass spectrometry-based assay for monitoring various kinases and comparing interspecies variability. Results showed species-specific differences in the kinome of the spleen, especially within certain kinase families. The study also demonstrated the application of these methods in studying species-specific inhibitor profiles.
JOURNAL OF PROTEOME RESEARCH
(2021)
Article
Multidisciplinary Sciences
Lauren Wegman-Points, Khaled Alganem, Ali Sajid Imami, Victoria Mathis, Justin Fortune Creeden, Robert McCullumsmith, Li-Lian Yuan
Summary: Protein kinases and their substrates form signaling networks across subcellular compartments, and assessing their activity in different fractions can provide insights into their functional roles. In this study, we used peptide arrays to evaluate the activity of serine/threonine protein kinases in synaptosomal, nuclear, and cytosolic fractions from rat frontal cortex. Our results showed differences in protein kinase activity among these fractions, and we identified enriched kinases in the synaptosomal fraction compared to the nuclear fraction. This study demonstrates the feasibility of using peptide arrays to assess subcellular fractions and reveals compartment-specific activity profiles associated with established and novel kinases.
SCIENTIFIC REPORTS
(2022)
Article
Plant Sciences
Jose Ribamar Costa Ferreira-Neto, Artemisa Nazare da Costa Borges, Manasses Daniel da Silva, David Anderson de Lima Morais, Joao Pacifico Bezerra-Neto, Guillaume Bourque, Ederson Akio Kido, Ana Maria Benko-Iseppon
Summary: This pioneering study analyzed genomic and transcriptomic data from Vigna unguiculata (cowpea) kinases, providing insights into their structural characteristics, evolution, conservation among Viridiplantae species, and gene expression under different stress situations. The study revealed mechanisms of genomic expansion, conservation patterns, and up-regulation of specific families of kinases in response to stress, laying the foundation for further research on the evolution and molecular function of VuPKs.
FRONTIERS IN PLANT SCIENCE
(2021)
Article
Chemistry, Medicinal
Zihao Shen, Yu-Hang Yan, Shuo Yang, Sang Zhu, Yuan Yuan, Zhiqiang Qiu, Huan Jia, Ruiqiong Wang, Guo-Bo Li, Honglin Li
Summary: Protein kinases play a central role in signal transduction and are important drug targets for therapeutic intervention. The ProfKin web server, based on the KinLigDB database, provides a versatile tool for structure-based kinase profiling, offering a wealth of information to guide drug discovery and development.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Nir Drayman, Jennifer K. DeMarco, Krysten A. Jones, Saara-Anne Azizi, Heather M. Froggatt, Kemin Tan, Natalia Ivanovna Maltseva, Siquan Chen, Vlad Nicolaescu, Steve Dvorkin, Kevin Furlong, Rahul S. Kathayat, Mason R. Firpo, Vincent Mastrodomenico, Emily A. Bruce, Madaline M. Schmidt, Robert Jedrzejczak, Miguel A. Munoz-Alia, Brooke Schuster, Vishnu Nair, Kyu-yeon Han, Amornrat O'Brien, Anastasia Tomatsidou, Bjoern Meyer, Marco Vignuzzi, Dominique Missiakas, Jason W. Botten, Christopher B. Brooke, Hyun Lee, Susan C. Baker, Bryan C. Mounce, Nicholas S. Heaton, William E. Severson, Kenneth E. Palmer, Bryan C. Dickinson, Andrzej Joachimiak, Glenn Randall, Savas Tay
Summary: This study identified a drug called masitinib that can inhibit the replication of both SARS-CoV-2 and OC43 virus, and acts by competitively inhibiting 3CLpro. The drug showed strong antiviral effects in in vivo experiments on mice infected with SARS-CoV-2, and was effective against multiple variants in vitro.
Article
Pharmacology & Pharmacy
Lingjie Bao, Zhe Wang, Zhenxing Wu, Hao Luo, Jiahui Yu, Yu Kang, Dongsheng Cao, Tingjun Hou
Summary: In this study, a model called AMGU was developed to predict the inhibitory activities of small molecules against various kinases. The AMGU model outperformed other models on both internal and external test sets, demonstrating its enhanced generalizability. Additionally, a method called edges masking was devised to explain the predictive mechanisms, and a web server called KIP was developed for predicting the polypharmacology effects of small molecules on the kinome.
ACTA PHARMACEUTICA SINICA B
(2023)
Article
Multidisciplinary Sciences
Hyejin Park, Sujeong Hong, Myeonghun Lee, Sungil Kang, Rahul Brahma, Kwang-Hwi Cho, Jae-Min Shin
Summary: Researchers proposed the AiKPro model, which combines structure-validated multiple sequence alignments and molecular 3D conformer ensemble descriptors to predict kinase-ligand binding affinities. The deep learning model uses an attention-based mechanism to capture complex patterns in kinase-ligand interactions. Evaluation showed good performance and robustness, potentially facilitating the discovery of novel interactions and selective inhibitors.
SCIENTIFIC REPORTS
(2023)
Article
Multidisciplinary Sciences
Marianna Krysinska, Bartosz Baranowski, Bartlomiej Deszcz, Krzysztof Pawlowski, Marcin Gradowski
Summary: In this study, using non-standard bioinformatic approaches, the researchers discovered 13 novel (pseudo)kinase families in the Legionella genus. They also analyzed the functional roles of these predicted kinases and found that some of them are present in other bacterial taxa, including other pathogens. This work highlights the ingenuity of nature in the pathogen-host arms race and provides a useful resource for the study of infection mechanisms.
SCIENTIFIC REPORTS
(2022)
Article
Oncology
Federica Fabro, Nynke M. Kannegieter, Erik L. de Graaf, Karla Queiroz, Martine L. M. Lamfers, Anna Ressa, Sieger Leenstra
Summary: Glioblastoma is the most deadly brain cancer with poor response to treatment. In this study, 2D and 3D models were used to investigate the effects of small protein kinase inhibitors on patient-derived glioblastoma. The results showed inter-patient variability in drug response, with the ErbB signaling pathway playing a role. It was also observed that the choice of model influenced the analysis of kinases. A new resistance mechanism derived from imatinib treatment was identified in one sample.
FRONTIERS IN ONCOLOGY
(2022)
Article
Cardiac & Cardiovascular Systems
Thierry Bove, Nicolas Bradt, Thomas Martens, Daniel De Wolf, Katrien Francois, Geoffroy de Beco, Thierry Sluysmans, Jean Rubay, Alain Poncelet
Summary: The study shows that the Ross operation provides children requiring aortic valve replacement with excellent survival prospects, but the dilation of autograft dimensions may increase the risk of reoperation.
ANNALS OF THORACIC SURGERY
(2021)
Article
Anesthesiology
Audrey Dieu, Victoria Van Regemorter, Thierry Detaille, Laurent Houtekie, Stephane Eeckhoudt, Celine Khalifa, David Kahn, Stephan Clement De Clety, Alain Poncelet, Mona Momeni
Summary: This study aimed to evaluate the effectiveness of using Multiplate and Rotem in guiding platelet transfusion after pediatric cardiac surgery, and to compare coagulation parameters between cyanotic and acyanotic patients. The results showed that Rotem was associated with platelet transfusion, while Multiplate results were not. Postoperative blood loss was significantly higher in the cyanotic group compared to the acyanotic group.
JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA
(2021)
Article
Cardiac & Cardiovascular Systems
Valerie Lacroix, David Kahn, Pascal Matte, Thierry Pieters, Philippe Noirhomme, Alain Poncelet, Arnaud Steyaert
Summary: This study prospectively studied 86 patients undergoing lobectomy and found that the robotic-assisted surgery group had better pulmonary function recovery and pain relief at 1 month, with no significant differences between the two groups at 2 and 6 months.
THORACIC AND CARDIOVASCULAR SURGEON
(2021)
Article
Health Care Sciences & Services
Maan Isabella Cajita, Kris Denhaerynck, Lut Berben, Fabienne Dobbels, Johan Van Cleemput, Maria Crespo-Leiro, Jan Van Keer, Alain Jean Poncelet, Cynthia Russell, Sabina De Geest
Summary: The study found that heart transplant centers with high-degree chronic illness management had significantly higher mean survival rates at 1 year post-transplantation compared to centers with low-degree chronic illness management, but no differences were observed at other time points. Patients at high-degree chronic illness management centers had lower odds of moderate to severe drinking. There were no significant associations between the degree of chronic illness management and other recommended health behaviors.
Article
Chemistry, Medicinal
Francesc Sabanes Zariquiey, Edgar Jacoby, Ann Vos, Herman W. T. van Vlijmen, Gary Tresadern, Jeremy Harvey
Summary: The combination of mixed-solvent molecular dynamics (MD) and time-structure independent component analysis (TICA) was applied to four retrospective case studies, and the results were compared with previous experimental and computational findings. It was found that the successful identification of cryptic pockets depends on the system and the cosolvent probes. The conformational state of the targets plays a critical role in docking studies with the parent ligands, which has implications for virtual screening applications.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Medicinal
Gary Tresadern, Kanaka Tatikola, Javier Cabrera, Lingle Wang, Robert Abel, Herman van Vlijmen, Helena Geys
Summary: In recent years, the prediction of binding affinity between protein and small molecules has greatly improved with the use of free energy methods. Methodological advancements have resulted in calculations that have an average unsigned error of less than 1 kcal/mol compared to experimental results. This article presents a statistical analysis on the implications of the variance in experimental and calculated binding affinities in relation to the true binding affinity. The findings suggest that unexpected outcomes may arise when evaluating prediction performance.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Medicinal
Vytautas Gapsys, David F. Hahn, Gary Tresadern, David L. Mobley, Markus Rampp, Bert L. de Groot
Summary: Currently, drug design projects can benefit from molecular dynamics simulations to predict protein-ligand binding free energy accurately. By utilizing workflows based on open source software packages, it is now possible to efficiently screen hundreds of compounds in a matter of days using pre-exascale computing resources.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Medicinal
Aldo Peschiulli, Daniel Oehlrich, Michiel Van Gool, Nigel Austin, Sven Van Brandt, Michel Surkyn, Michel De Cleyn, Ann Vos, Gary Tresadern, Frederik J. R. Rombouts, Gregor J. Macdonald, Diederik Moechars, Andres A. Trabanco, Harrie J. M. Gijsen
Summary: This study describes further work on prototypes of heteroaryl-fused piperazine inhibitors of BACE1, aiming to modulate their basicity and reduce binding to the hERG channel. The researchers identified compound 36, which demonstrated nanomolar potency, cardiovascular safety, and oral bioavailability, and effectively reduced A beta(42) levels in animal models.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Cardiac & Cardiovascular Systems
Yannick Kabulo Kolela, Maureen Klepper, Geoffroy de Beco, Thierry Sluysmans, Alain Poncelet
Summary: This case report highlights a rare case of a child who underwent ASO in the neonatal period with a coronary artery (LAD) described as atretic left in place. At the age of seven, the patient developed myocardial ischemia due to retrograde flow from the LAD into the pulmonary artery, leading to a late LAD reimplantation. The case emphasizes the importance of translocating even very small ostia during ASO.
CONGENITAL HEART DISEASE
(2022)
Article
Cardiac & Cardiovascular Systems
Veronica Lorenz, Karlien Carbonez, Geoffroy de Beco, Alain Poncelet
Summary: This study reports a rare case of mediastinitis and infective endocarditis occurring 8 months after Melody valve implantation, which was successfully treated with the implantation of a homograft to reconstruct the right ventricular outflow tract.
CONGENITAL HEART DISEASE
(2022)
Article
Chemistry, Physical
Yuriy Khalak, Gary Tresadern, David F. Hahn, Bert L. de Groot, Vytautas Gapsys
Summary: This research explores the combination of active learning protocol with first-principles based alchemical free energy calculations to identify high affinity PDE2 inhibitors. By explicitly evaluating only a small fraction of compounds in a large chemical library, we have successfully developed an efficient protocol.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Chemistry, Medicinal
Mary Pitman, David F. Hahn, Gary Tresadern, David L. Mobley
Summary: Drug discovery is accelerated using computational methods such as alchemical simulations to estimate ligand affinities. Recent research shows that optimizing the statistical architecture of perturbation graphs improves the accuracy of predicted changes in ligand binding energy. To improve the success rate of computational drug discovery, we present the open-source software package HiMap, which is a new version of its predecessor LOMAP.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Sridip Parui, James C. Robertson, Sandeep Somani, Gary Tresadern, Cong Liu, Ken A. Dill
Summary: The study developed the MELD-Bracket method for efficient affinity ranking of structurally diverse small molecule ligands in structure-based drug discovery. The method was tested on multiple protein systems and showed a balanced accuracy and computational efficiency in ranking different ligands.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Medicine, General & Internal
Stefano Mastrobuoni, Manuel Johanns, Martial Vergauwen, Gwen Beaurin, Mark Rider, Pierre Gianello, Alain Poncelet, Olivier Van Caenegem
Summary: Transplantation of heart following donation after circulatory death (DCD) has been introduced into clinical practice. In a porcine model of DCD heart, we tested the effect of different temperatures on cardiac metabolism during ex vivo reperfusion. We observed a steep fall in ATP concentrations at the end of warm ischemic time, limited regeneration during reperfusion, and an increase in lactate concentration. However, the temperature did not have an effect on ATP or lactate concentration. Additionally, all cardiac allografts experienced significant weight increase due to cardiac edema, regardless of the temperature.
JOURNAL OF CLINICAL MEDICINE
(2023)
Article
Chemistry, Physical
Hannah M. Baumann, Eric Dybeck, Christopher L. McClendon, Frank C. Pickard, Vytautas Gapsys, Laura Perez-Benito, David F. Hahn, Gary Tresadern, Alan M. Mathiowetz, David L. Mobley
Summary: Binding free energy calculations are used to predict the potency of compounds binding to protein sites in a physically rigorous manner. Relative binding free energy (RBFE) calculations are commonly used but limited by the requirement of ligands sharing a common scaffold and binding mode. Absolute binding free energy (ABFE) calculations are an alternate method for non-congeneric ligands but suffer from long convergence times. The SepTop method overcomes the limitations of both RBFE and ABFE methods by allowing large scaffold changes between ligands with comparable convergence time. It provides a more efficient and flexible approach for ranking ligands in drug design.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Review
Pharmacology & Pharmacy
Karlie R. Sharma, Christine M. Colvis, Griffih P. Rodgers, Douglas M. Sheeley
Summary: There are many genes within the druggable genome that have not been studied, and the US National Institutes of Health's program provides resources to explore these genes, with the potential for rapid impact on human health.
DRUG DISCOVERY TODAY
(2024)
Review
Pharmacology & Pharmacy
Mohammad Sameer Khan, B. H. Jaswanth Gowda, Waleed H. Almalki, Tanuja Singh, Amirhossein Sahebkar, Prashant Kesharwani
Summary: Mitochondria-specific functional liposomes hold great potential for cancer therapy. This review discusses the association between mitochondria and tumor formation, as well as the advantages of liposomes in delivering drugs to mitochondria.
DRUG DISCOVERY TODAY
(2024)
Review
Pharmacology & Pharmacy
Choong Yong Ung, Cristina Correia, Hu Li, Christopher M. Adams, Jennifer J. Westendorf, Shizhen Zhu
Summary: With increasing human life expectancy, the global medical burden of chronic diseases is growing. Chronic diseases often involve malfunctioning of multiple organs, and understanding the interorgan crosstalk is crucial to understanding the etiology of chronic diseases. Researchers have proposed the locked-state model (LoSM) and cutting-edge systems biology and artificial intelligence strategies to decipher chronic multiorgan locked states. The findings have important clinical implications for improving treatments for chronic diseases.
DRUG DISCOVERY TODAY
(2024)
