Article
Chemistry, Medicinal
Woochan Kim, Sun-Mi Lee, Pyeong-Hwa Jeong, Jae-Hoon Jung, Yong-Chul Kim
Summary: In this study, novel 4-(1,5or 2,5-triazole)-pyrrolopyrimidine derivatives with aromatic moieties were synthesized as JAK1 inhibitors, and an in vitro enzyme assay was used to evaluate the JAK inhibitory effects. Among these JAK1 inhibitors, compound 23a showed high JAK1 selectivity with a key interaction between the iodine atom of compound 23a and His-885 of hJAK1.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(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.
Article
Chemistry, Medicinal
Sean P. Henry, William L. Jorgensen
Summary: The Janus kinases (JAKs) play important roles in the JAK-STAT signaling pathway and are involved in various physiological processes. Although they are targeted by FDA-approved drugs, these drugs often have adverse effects due to their inhibition of JAK kinase activity. However, JAKs have a unique pseudokinase domain (JH2) that regulates the adjacent kinase domain (JH1). Targeting the JH2 domain may provide an alternative approach to modulate JAKs without the associated adverse effects. The recent FDA approval of deucravacitinib, a JH2 ligand, for treating plaque psoriasis demonstrates the potential of this strategy.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Afzal Hussain, Ashfaq Hussain, Nazmiara Sabnam, Chandan Kumar Verma, Namita Shrivastava
Summary: The CDK-activating complex (CAK) drives cell cycle advancement by phosphorylating cell cycle CDKs. CDK7 is a potential therapeutic target for malignant tumors, and DB07075 is a promising inhibitor for CDK7 kinase.
ARABIAN JOURNAL OF CHEMISTRY
(2023)
Review
Oncology
Juuli Raivola, Teemu Haikarainen, Bobin George Abraham, Olli Silvennoinen
Summary: The JAK/STAT pathway is crucial for immune cell development and function, with mutations linked to hematological diseases like leukemia. Current therapeutic strategies target the pathway's aberrant activation, with FDA-approved JAK inhibitors showing promise in treating autoimmune diseases and blood cancers. However, there is a need for more effective JAK modulators to fully harness their potential in leukemia treatment.
Article
Pharmacology & Pharmacy
Huizhen Ge, Lizeng Peng, Zhou Sun, Huanxiang Liu, Yulin Shen, Xiaojun Yao
Summary: In this study, novel HPK1 inhibitors were identified using virtual screening and kinase inhibition assays. Molecular dynamics simulations were performed to analyze the interaction between the identified compounds and HPK1 kinase domain. The most potent compound showed potential for further development as an HPK1 inhibitor for immunotherapy.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Naomi Scarano, Elena Abbotto, Francesca Musumeci, Annalisa Salis, Chiara Brullo, Paola Fossa, Silvia Schenone, Santina Bruzzone, Elena Cichero
Summary: This article focuses on the selective inhibitors of SIRT2 enzyme. By using SBVS method, a potential molecular scaffold for designing new SIRT2 inhibitors was identified. Experimental results showed that this molecular scaffold exhibited strong SIRT2 inhibitory activity, validating the effectiveness of the research strategy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Andrei-Flavius Radu, Simona Gabriela Bungau, Andrei Paul Negru, Bogdan Uivaraseanu, Mihaela Alexandra Bogdan
Summary: Rheumatoid arthritis (RA) is a severe autoimmune disease that affects millions of patients worldwide. Despite recent improvements, there are still unmet needs in the treatment of RA. In this study, in silico research was conducted to identify potential active molecules for the treatment of RA. The findings suggest that further research is needed to validate the efficacy and safety profiles of the most promising candidates.
Article
Biochemistry & Molecular Biology
Ruijuan Liu, Xuewei Liu
Summary: Through structure-based virtual screening, this study identified 47 potential inhibitors of HK-II, with nine compounds showing high cytotoxicity to cancer cells. Two compounds demonstrated significant inhibitory effects on the HK-II enzyme, suggesting potential for future tumor therapy.
Article
Biochemistry & Molecular Biology
Chun-Chun Chang, Sheng-Feng Pan, Min-Huang Wu, Chun-Tse Cheng, Yan-Rui Su, Shinn-Jong Jiang, Hao-Jen Hsu
Summary: This study focused on the abnormal Wnt signaling pathway and found that the inhibition of tankyrase (TNKS) activity can reduce cancer cell growth, invasion, and resistance to treatment. Through pharmacophore search and docking, potential TNKS inhibitors were identified and two of them were validated as promising inhibitors. Additionally, a cell-based assay revealed that one of the inhibitors is the most likely TNKS inhibitor and can effectively inhibit the growth of colorectal cancer cells.
Article
Chemistry, Medicinal
Wenqing Zhang, Kan Li, Tianqi Wang, Ming Wu, Linli Li
Summary: This study identified seven JMJD7 inhibitors using consensus docking/scoring strategy and bioactivity evaluation, with Cpd-3 being the most potent compound showing efficient binding to JMJD7 in vitro and displaying good inhibitory activity against cancer cell lines expressing high levels of JMJD7. Overall, this research provided a solid foundation for drug discovery targeting JMJD7.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Chia-Wei Weng, Chi-Hsuan Wei, Jeng-Yuan Tsai, Yi-Hua Lai, Gee-Chen Chang, Jeremy J. W. Chen
Summary: In this study, a hybrid virtual screening approach was used to identify a compound with significant inhibitory effects on EGFR activity, and its mechanism of action in lung cancer cells was investigated.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Sathya Babu, Santhosh Kumar Nagarajan, Sruthy Sathish, Vir Singh Negi, Honglae Sohn, Thirumurthy Madhavan
Summary: In this study, ligand-based pharmacophore modeling combined with virtual screening and molecular docking methods was used to identify potent and selective lead compounds for JAK1. The identified compounds showed good potency and selectivity compared to the drug ruxolitinib, and further validation using in vitro and in vivo methods is recommended.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Chemistry, Medicinal
Yan Chen, Hui Li, Rose Yen, Thilo J. Heckrodt, Darren McMurtrie, Rajinder Singh, Vanessa Taylor, Esteban S. Masuda, Gary Park, Donald G. Payan
Summary: This study discovered a series of potent JAK1 inhibitors with selectivity over JAK2 and discussed the unique correlation between a trifluoromethyl group and CYP3A4 inhibition. Cell-based assays and biochemical and additional cellular assays were used to evaluate the potency and selectivity of the lead molecules, and novel synthetic routes were developed for the discovery of late-stage lead molecules.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Biochemistry & Molecular Biology
Tanaporn Uengwetwanit, Nopporn Chutiwitoonchai, Kanin Wichapong, Nitsara Karoonuthaisiri
Summary: This study analyzed the amino acid sequence conservation of RNA-dependent RNA polymerase (RdRp) across coronaviruses and identified compounds with promising antiviral activity. Molecular dynamics simulations and binding free-energy calculations were performed to elucidate critical interactions, providing a foundation for developing lead compounds effective against SARS-CoV-2.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2022)
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)
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
Multidisciplinary Sciences
Ilona Bereczki, Vladimir Vimberg, Eszter Lorincz, Henrietta Papp, Lajos Nagy, Sandor Keki, Gyula Batta, Ana Mitrovic, Janko Kos, Aron Zsigmond, Istvan Hajdu, Zsolt Lorincz, David Bajusz, Laszlo Petri, Jan Hodek, Ferenc Jakab, Gyorgy M. Keseru, Jan Weber, Lieve Naesens, Pal Herczegh, Aniko Borbas
Summary: Patients infected with SARS-CoV-2 are at risk of co-infection with Gram-positive bacteria, which greatly affects their prognosis. Antimicrobial drugs with dual antiviral and antibacterial activity would be valuable in this context. The researchers synthesized and evaluated seven derivatives of teicoplanin, a glycopeptide antibiotic, with hydrophobic or superbasic side chains. Except for one derivative, all teicoplanin derivatives effectively inhibited SARS-CoV-2 replication in VeroE6 cells. Some of these derivatives also showed activity against HCoV-229E, a human coronavirus, in human Calu-3 cells. The study revealed that the teicoplanin derivatives efficiently prevented the entry of SARS-CoV-2 into cells through both endosomal and surface entry routes. Moreover, these derivatives exhibited good to excellent activity against Gram-positive bacteria resistant to glycopeptide antibiotics.
SCIENTIFIC REPORTS
(2022)
Article
Parasitology
Katalin Toth, Sevan Alwan, Susan Khan, Stanton F. McHardy, Philip T. LoVerde, Michael D. Cameron
Summary: The antischistosomal drug OXA requires activation by a sulfotransferase within the parasitic worm for killing. However, its clinical plasma concentrations are much lower than the in vitro efficacious concentration for schistosomal killing. By modeling the pharmacokinetic data, it was determined that the parasite resides in the vasculature between the intestine and the liver, which explains the required human dose. In silico models and follow-up PK studies in mice confirmed the dose needed to recapitulate human conditions.
INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE
(2023)
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
Biochemistry & Molecular Biology
Andre Schutzer Godoy, Aline Minalli Nakamura, Alice Douangamath, Yun Song, Gabriela Dias Noske, Victor Oliveira Gawriljuk, Rafaela Sachetto Fernandes, Humberto D. Muniz Pereira, Ketllyn Irene Zagato Oliveira, Daren Fearon, Alexandre Dias, Tobias Krojer, Michael Fairhead, Alisa Powell, Louise Dunnet, Jose Brandao-Neto, Rachael Skyner, Rod Chalk, David Bajusz, Miklos Bege, Aniko Borbas, Gyoergy Miklos Keseru, Frank von Delft, Glaucius Oliva
Summary: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). The NSP15 endoribonuclease enzyme, known as NendoU, plays a critical role in the virus's ability to evade the immune system and is a potential target for antiviral drug development. However, the complexity of NendoU's structure and kinetics, as well as the lack of structural complexes, hinder the development of inhibitors.
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.
Article
Biochemistry & Molecular Biology
Evelyn Incze, Katalin Mango, Ferenc Fekete, Adam Ferenc Kiss, Adam Poti, Tuende Harko, Judit Moldvay, David Szuts, Katalin Monostory
Summary: Resistance to anticancer agents is a major problem in tumor therapy, and genetic polymorphisms and copy number alterations of drug-metabolizing enzymes contribute to the development of resistance. A high-throughput qPCR-based method was used to detect CYP copy number alterations in tumors, and the altered copy numbers of specific CYP genes were associated with non-responder patients. This method could be an alternative to next-generation sequencing and provide a potential biomarker for therapy-resistant tumors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
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)
