Article
Biochemistry & Molecular Biology
Parthasaradhireddy Tanguturi, Vibha Pathak, Sixue Zhang, Omar Moukha-Chafiq, Corinne E. Augelli-Szafran, John M. Streicher
Summary: The study successfully developed novel inverse agonists and irreversible antagonists for the delta opioid receptor, providing new tools to investigate its biology or potential therapeutics.
Article
Pharmacology & Pharmacy
Laura Grohs, Linhan Cheng, Saskia Coenen, Bassam G. Haddad, Astrid Buelow, Idil Toklucu, Lisa Ernst, Jannis Koerner, Guenther Schmalzing, Angelika Lampert, Jan-Philipp Machtens, Ralf Hausmann
Summary: This study found that NSAIDs can inhibit P2X3R and P2X2/3R subtypes, with Diclofenac being the most effective antagonist. The inhibition is mainly achieved through interaction with residues of the ATP-binding site. However, considering the rarely reached concentrations in therapeutic doses, the analgesic effect of NSAIDs may be minor compared to their high-potency cyclooxygenase inhibition.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Neurosciences
Xin Li, Zhuo-Jun Du, Jun-Nan Xu, Zhi-Man Liang, Song Lin, Hao Chen, Shu-Ji Li, Xiao-Wen Li, Jian-Ming Yang, Tian-Ming Gao
Summary: Pharmacological manipulation of mGluR5 suggests its involvement in anxiety disorders, but the mechanism behind its role in stress-induced anxiety-like behavior is unclear. This study found that chronic restraint stress and mGluR5 knockdown lead to anxiety-like behavior and impaired inhibitory synaptic inputs in hippocampal CA1 pyramidal neurons. However, positive allosteric modulator of mGluR5 can rescue anxiety-like behavior and restore inhibitory synaptic inputs. These findings highlight the essential role of mGluR5 in mediating stress-induced anxiety-like behavior in hippocampal CA1 pyramidal neurons.
NEUROPSYCHOPHARMACOLOGY
(2023)
Article
Pharmacology & Pharmacy
Isabel Hamshaw, Marco M. D. Cominetti, Wing-Yee Lai, Mark Searcey, Anja Mueller
Summary: Cancer metastasis is a major cause of cancer-related death. The CXCR4 receptor and its ligand CXCL12 play important roles in promoting metastasis, making them attractive therapeutic targets. In this study, a novel CXCR4 antagonist was developed and used for CXCR4-based imaging. The results showed that these antagonists were non-toxic and effectively inhibited cancer cell migration and calcium release.
BIOCHEMICAL PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Carmine Marco Morgillo, Antonio Lupia, Alessandro Deplano, Luciano Pirone, Bianca Fiorillo, Emilia Pedone, F. Javier Luque, Valentina Onnis, Federica Moraca, Bruno Catalanotti
Summary: FAAH is a key enzyme in controlling cannabinoid signaling, and research on the mechanism of action of the non-competitive inhibitor TPA14 has provided a theoretical basis for the design of effective drugs for the treatment of neuropathic pain and chronic inflammation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Nathan Farrokhian, Jeff Maltas, Mina Dinh, Arda Durmaz, Patrick Ellsworth, Masahiro Hitomi, Erin McClure, Andriy Marusyk, Artem Kaznatcheev, Jacob G. Scott
Summary: In this study, the frequency-dependent interactions between a gefitinib-resistant non-small cell lung cancer population and its sensitive ancestor were measured experimentally. The cost of resistance was found to be insufficient in predicting competitive exclusion, and frequency-dependent growth rate measurements were necessary. Simulations showed that ecological growth effects can influence the predicted extinction time.
Article
Chemistry, Physical
Roya Momen, Alireza Azizi, Alejandro Morales-Bayuelo, Mehdi Pazhoohesh, Xiaobo Ji
Summary: This study investigates torquoselectivity in three thermal cyclobutene ring-opening reactions using various theoretical analyses. It reveals that one reaction is competitive while the other two are non-competitive, in agreement with experimental results. Through QTAIM and stress tensor frameworks, the research provides a better understanding of reaction mechanisms.
JOURNAL OF CHEMICAL PHYSICS
(2021)
Article
Biology
Amichai Baichman-Kass, Tingting Song, Jonathan Friedman
Summary: Microorganisms in diverse communities are influenced by interspecific interactions, and the joint effects of multiple species on a single species remain largely unknown. In a study, thousands of bacterial communities were assayed, revealing that the joint effects of multiple species on a focal species are often dominated by the strongest individual-species effect. This finding is significant for understanding the introduction of species into occupied environments and has implications in fields such as medicine, agriculture, and ecology.
Article
Cell Biology
Miguel A. Gonzalez-Lozano, Joke Wortel, Rolinka J. van der Loo, Jan R. T. van Weering, August B. Smit, Ka Wan Li
Summary: The study dissected the molecular synaptic modulation mediated by mGluR5 using genetic and pharmacological mouse models, revealing a connection between mGluR5 and the modulation of synaptic mitochondrial function. This finding suggests a potential role of mGluR5 as a mediator between synaptic activity and mitochondrial function.
Article
Multidisciplinary Sciences
Alice Wong, Garance Merholz, Uri Maoz
Summary: By studying human random-sequence generation during a competitive Rock-Paper-Scissors game, it was found that human RSG can reach levels statistically indistinguishable from computer pseudo-random generators. However, explicitly informing participants to be as random as possible to win the game does not further improve human RSG, and the higher level of RSG in the game setting does not transfer outside the game environment.
SCIENTIFIC REPORTS
(2021)
Article
Chemistry, Multidisciplinary
Sai Krishna Katla, Chenyu Lin, Juan Perez-Mercader
Summary: The competitive exclusion principle states that two species occupying the same niche will compete with each other, leading to the exclusion of one species. We conducted competition experiments between two populations of artificial protocells and found that competition still occurs even without biochemical functionality. This has significant implications for protocell research, the origin and early evolution of life, and the laboratory synthesis of life, as well as the potential presence and evolution of generalized life in exoplanets.
CELL REPORTS PHYSICAL SCIENCE
(2023)
Article
Sport Sciences
Rebecca A. Dowse, Josh L. Secomb, Michaela Bruton, Sophia Nimphius
Summary: The study found that senior-elite surfers have significantly better ankle proprioception and range of motion compared to other groups; however, the relationship between years of surf-specific experience and ankle proprioception is weak. Additionally, senior-elite surfers showed better drop-and-stick performance.
JOURNAL OF SCIENCE AND MEDICINE IN SPORT
(2021)
Article
Multidisciplinary Sciences
Rungroj Krittayaphong, Thanita Boonyapiphat, Suchart Aroonsiriwattana, Pornchai Ngamjanyaporn, Gregory Y. H. Lip
Summary: This study aimed to determine the causes of death in Asian non-valvular atrial fibrillation (AF) patients registered in a nationwide AF registry, and investigate the differences in causes of death between AF patients who were taking and not taking oral anticoagulant (OAC). The COOL-AF study in Thailand enrolled 3,405 non-valvular AF patients and found that non-cardiovascular death, such as infection/sepsis or malignancy, was more prevalent than cardiovascular death in Asian AF patients. Thus, an improved integrated care approach is needed to reduce non-cardiovascular death in Asian AF patients.
Article
Psychology, Social
Uriel Haran, Dina Van Dijk, Michal Barina, Mor Krief, Stav Rosenzweig
Summary: This study examines the relationship between guilt proneness, general motivation, and competitive motivation. The results show that guilt proneness is positively related to general motivation but negatively related to competitive motivation. Guilt-prone individuals are less likely to pursue competitive paths and prefer non-competitive strategies, while emphasizing prosocial aspects of competitiveness can attenuate these effects.
JOURNAL OF PERSONALITY
(2023)
Review
Cardiac & Cardiovascular Systems
Arjun K. Pandey, Deepak L. Bhatt, Francesco Cosentino, Nikolaus Marx, Ori Rotstein, Bertram Pitt, Ambirash Pandey, Javed Butler, Subodh Verma
Summary: Despite current treatment options, patients with heart failure and chronic kidney disease (CKD) remain at high risk for adverse outcomes and disease progression. Non-steroidal mineralocorticoid receptor antagonists (MRAs) have emerged as a new dimension in the treatment of cardiorenal disease, offering unique pharmacological properties and benefits. These agents have anti-inflammatory, anti-remodelling, and anti-fibrotic effects in the heart, kidneys, and blood vessels. Although there are several non-steroidal MRAs in development, only esaxerenone and finerenone have been approved globally.
EUROPEAN HEART JOURNAL
(2022)
Review
Chemistry, Physical
Levente M. Mihalovits, Gyorgy G. Ferenczy, Gyorgy M. Keseru
Summary: The recent rise of targeted covalent inhibitors in drug discovery presents new opportunities and challenges for quantum chemical reactivity calculations. These calculations are crucial in determining inhibitory potency by predicting intrinsic reactivities of covalent ligands. Mixed quantum mechanical/molecular mechanical potentials provide a comprehensive description of covalent ligand binding mechanisms, while efficient QM/MM predictions of ligand reactivities are highly useful in covalent drug discovery.
INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Anita Racz, Roberta Palko, Dorottya Csanyi, Zsuzsanna Riedl, David Bajusz, Gyorgy M. Keseru
Summary: This study discovered a series of new MELK inhibitors through virtual screening, and disclosed the synthesis and bioactivity of this class of compounds for the first time, providing a new direction for anti-cancer drug development.
Review
Pharmacology & Pharmacy
Nikolett Peczka, Zoltan Orgovan, Peter Abranyi-Balogh, Gyorgy Miklos Keseru
Summary: This review provides an overview of electrophilic warheads used for protein labeling in chemical biology and medicinal chemistry. The warheads are discussed based on targeted residues, mechanism, and selectivity, and analyzed using multiple datasets. Despite the availability of numerous electrophilic warheads, only a fraction of them are used in current drug discovery projects. Recent studies have identified new tractable residues, but the discovery of new warheads for these residues is still needed.
EXPERT OPINION ON DRUG DISCOVERY
(2022)
Article
Pharmacology & Pharmacy
Krisztina Kiss, Kristof Hegedus, Panna Vass, Diana Vari-Mezo, Attila Farkas, Zsombor Kristof Nagy, Laszlo Molnar, Jozsef Tovari, Gabor Mezo, Gyorgy Marosi
Summary: Special formulations were developed to enhance the water solubility of curcuminoids, leading to the preparation of fast-dissolving fibrous dosage forms for intravenous infusion. The antitumor activity of the curcuminoid complexes with HP-beta-CD was found to be similar or better compared to free APIs.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2022)
Review
Pharmacology & Pharmacy
David Bajusz, Gyorgy M. Keseru
Summary: Experimental and virtual screening are complementary approaches that should be integrated in lead discovery settings. Virtual screening can access extremely large synthetically feasible chemical space that can be effectively searched on GPU clusters or cloud architectures. Experimental screening provides reliable datasets by quantitative HTS applications, and DNA-encoded libraries (DEL) have enlarged the chemical space covered by these technologies. These developments, together with the use of artificial intelligence methods, represent new options for their efficient integration. The case studies discussed here demonstrate the benefits of complementary strategies, such as focused and iterative screening.
EXPERT OPINION ON DRUG DISCOVERY
(2022)
Article
Chemistry, Medicinal
Amanda E. Wakefield, David Bajusz, Dima Kozakov, Gyoergy M. Keseru, Sandor Vajda
Summary: Despite the limited number of GPCR structures cocrystallized with allosteric inhibitors, protein mapping has revealed the presence of druggable sites at the same locations in a large variety of GPCRs. These sites cluster at nine distinct locations and can be specifically targeted for allosteric modulation across GPCRs. The FTMap server facilitates protein mapping and is freely available for academic and governmental use.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Physiology
Bence Tamas Varga, Attila Gaspar, Aliz Judit Ernyey, Barbara Hutka, Brigitta Tekla Tajti, Zoltan Sandor Zadori, Istvan Gyertyan
Summary: The aim of this study was to establish a pharmacologically induced neurovascular uncoupling (NVU) method in rats as a model of human cognitive decline. The researchers successfully induced NVU in rats using a pharmacological cocktail, but it also caused adverse side effects such as hypertension and intestinal malformations. However, the treatment did not impair cognitive performance in the rats. Further refinements are needed for the development of a more applicable model.
PHYSIOLOGY INTERNATIONAL
(2022)
Article
Chemistry, Organic
Peter Szemesi, Peter Bana, Zoltan Szakacs, Istvan Greiner, Janos Eles
Summary: Aril azides are commonly used in laboratories but their explosive properties limit their application on a larger scale. Flow chemistry provides a safer method for the synthesis and utilization of dangerous and explosive chemicals. This study successfully achieved the safe syntheses of various derivatives within a continuous-flow system.
CURRENT ORGANIC CHEMISTRY
(2022)
Article
Biochemical Research Methods
Krisztina Kiss, Soma Ranky, Zsuzsanna Gyulai, Laszlo Molnar
Summary: This paper introduces a Tecan add-on peptide synthesizer (TaPSy) that is flexible, cost-effective, and capable of parallel synthesis of multiple peptides.
Article
Chemistry, Medicinal
Peter Abranyi-Balogh, Aaron Keeley, Gyorgy G. Ferenczy, Laszlo Petri, Timea Imre, Katarina Grabrijan, Martina Hrast, Damijan Knez, Janez Ilas, Stanislav Gobec, Gyorgy M. Keseru
Summary: The second generation of heterocyclic electrophiles, the quaternized analogue of the heterocyclic covalent fragment library, showed improved reactivity and MurA inhibitory potency. Quantum chemical reaction barrier calculations, GSH reactivity assay, and thrombin counter screen were used to explain the improved reactivity and selectivity of the N-methylated heterocycles and compare the two generations of heterocyclic electrophiles.
Article
Biochemistry & Molecular Biology
Laszlo Petri, Peter Aabranyi-Balogh, Noemi Csorba, Aaron Keeley, Jozsef Simon, Ivan Randelovic, Jozsef Tovari, Gitta Schlosser, Daniel Szabo, Laszlo Drahos, Gyoergy M. Keseru
Summary: SuFEx chemistry is based on the unique reactivity of the sulfonyl fluoride group with a range of nucleophiles. Sulfonyl fluorides can label multiple nucleophilic amino acid residues, making them popular in both chemical biology and medicinal chemistry applications. In this study, a small sulfonyl fluoride library was synthesized and characterized, resulting in the identification of a 3-carboxybenzenesulfonyl fluoride warhead for tagging nucleophilic residues. Coupling diverse fragments to this warhead could yield a library of sulfonyl fluoride bits (SuFBits) for screening against protein targets, facilitated by mass spectrometry identification of weak fragments.
Article
Biochemistry & Molecular Biology
David Bajusz, Gaspar Pandy-Szekeres, Agnes Takacs, Elvin D. de Araujo, Gyorgy M. Keseru
Summary: SH2db is a comprehensive structural database and webserver for SH2 domain structures, providing search, browse, and download functions. It assists researchers in their day-to-day work and serves as a valuable resource for SH2 domain-related research.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Chemistry, Physical
Levente M. Mihalovits, Levente Kollar, David Bajusz, Damijan Knez, Kristof Bozovicar, Timea Imre, Gyorgy G. Ferenczy, Stanislav Gobec, Gyorgy M. Keseru
Summary: This study investigates the mechanism of covalent labeling of cysteines using heterocyclic thiones as reversible covalent warheads. The main protease of SARS-CoV-2 harboring Cys145 was chosen as the target, and molecular dynamics simulations and experimental validations were conducted.
Review
Pharmacology & Pharmacy
Noemi Csorba, Peter Abranyi-Balogh, Gyorgy M. Keseru
Summary: Covalent fragment approaches combine the advantages of covalent binders and fragment-based drug discovery (FBDD) for target identification and validation. Recent studies have expanded the chemistries of different warheads to target protein nucleophiles other than cysteine residues. This review discusses these newly developed amino-acid-specific and promiscuous warheads, as well as emerging labeling chemistries. The applications of covalent fragments in the development of molecular glues and proteolysis-targeting chimeras (PROTACs) are highlighted, along with their utility in chemical proteomics-based target identification and validation.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2023)
Article
Chemistry, Organic
Andras Gy. Nemeth, Renata Szabo, Krisztina Nemeth, Gyorgy M. Keseru, Peter Abranyi-Balogh
Summary: This study discovered the reactivity of easily accessible electron deficient alkenes towards sulfur and developed a new pseudo-multicomponent reaction for the preparation of polysulfides.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
