Article
Biochemistry & Molecular Biology
Shuaishuai Xing, Ying Chen, Baichen Xiong, Weixuan Lu, Qi Li, Yuanyuan Wang, Mengxia Jiao, Feng Feng, Yao Chen, Wenyuan Liu, Haopeng Sun
Summary: 2513-4169, a promising lead compound, shows potential inhibitory activity and neuroprotective effect for treating Alzheimer's disease.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2021)
Article
Biochemistry & Molecular Biology
Xin-Yu Leng, Shuang Gao, Yi-Fan Ma, Li-Xia Zhao, Meng Wang, Fei Ye, Ying Fu
Summary: This study generated two pharmacophore models for virtual screening of HPPD inhibitors and successfully identified four compounds with high energy, good solubility, and safety properties. Three novel HPPD inhibitors were designed and synthesized, one of which demonstrated similar inhibition and herbicidal activity as mesotrione, with better crop safety. The properties of these compounds were found to be superior to mesotrione, making them potential candidates for novel HPPD inhibitor herbicides.
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
(2023)
Article
Chemistry, Medicinal
Anupreet Kharbanda, Lingtian Zhang, Debasmita Saha, Phuc Tran, Ke Xu, Ming O. Li, Yuet-Kin Leung, Brendan Frett, Hong-yu Li
Summary: TGF beta plays a crucial role in maintaining the homeostasis of epithelial and neural tissues, wound repair, and immune responses. Dysregulation of TGF beta is associated with various diseases, with modifying the tumor microenvironment being of significant clinical interest. Despite efforts, there is currently no FDA-approved therapy to inhibit the TGF beta pathway, but targeting TGF beta RI kinase remains a major approach.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biology
Maryam Nazari, Elham Rezaee, Roshanak Hariri, Tahmineh Akbarzadeh, Sayyed Abbas Tabatabai
Summary: The study synthesized a series of 1,2,4-oxadiazole compounds, among which compound 6n exhibited the highest potency and selectivity towards BuChE enzyme, potentially serving as new oral anti-Alzheimer's agents. The docking analysis showed that compound 6n properly fits the active site pocket of BuChE enzyme, forming desirable lipophilic interactions and hydrogen bonds. Additionally, in silico ADME studies suggested that these compounds have promising potential for development as new oral anti-Alzheimer's agents.
Article
Chemistry, Medicinal
Jifa Zhang, Lun Tan, Chengyong Wu, Yuyan Li, Hao Chen, Yinghuan Liu, Yuxi Wang
Summary: Novel 4,6-pyrimidine analogues were synthesized as colchicine binding site inhibitors (CBSIs) with strong antiproliferative activities. Among them, compound 17j showed the most potent activities against 6 human cancer cell lines, with IC50 values ranging from 1.1 nM to 4.4 nM, which was 76 times higher than the lead compound 3 in A549 cells. The co-crystal structure confirmed the key binding mode of 17j at the colchicine binding site. Furthermore, 17j inhibited tubulin polymerization, depolymerized cellular microtubules, induced G2/M arrest, inhibited cell migration, and promoted apoptosis. In vivo, 17j effectively inhibited primary tumor growth in the A549 xenograft model, with tumor growth inhibition rates of 42.51% (5 mg/kg) and 65.42% (10 mg/kg). Overall, 17j represents a promising new generation of CBSIs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Alicja Skrzypek, Joanna Matysiak, Monika Karpinska, Kamila Czarnecka, Pawel Krecisz, Dorota Stary, Jedrzej Kukulowicz, Beata Paw, Marek Bajda, Pawel Szymanski, Andrzej Niewiadomy
Summary: Two series of novel 1,3,4-thiadiazole-resorcinol conjugates were efficiently synthesized and evaluated as cholinesterases inhibitors, showing potential as mixed type inhibitors with good affinity for both AChE and BuChE. These compounds exhibited better inhibition of Aβ aggregation and antioxidant properties compared to curcumin, with metal ion chelating properties and acceptable cytotoxicity in vitro.
BIOORGANIC CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Qiuping Xiang, Guolong Luo, Cheng Zhang, Qingqing Hu, Chao Wang, Tianbang Wu, Hongrui Xu, Jiankang Hu, Xiaoxi Zhuang, Maofeng Zhang, Shuang Wu, Jinxin Xu, Yan Zhang, Jinsong Liu, Yong Xu
Summary: TRIM24 and BRPF1 are epigenetics readers and potential therapeutic targets. The compound 20l is a new dual inhibitor of TRIM24/BRPF1, with inhibitory effects on prostate cancer cells and tumor growth in animal models, showing potential for further development as a more potent inhibitor.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Dawid Panek, Anna Pasieka, Gniewomir Latacz, Paula Zareba, Michal Szczech, Justyna Godyn, Fabien Chantegreil, Florian Nachon, Xavier Brazzolotto, Anna Skrzypczak-Wiercioch, Maria Walczak, Magdalena Smolik, Kinga Salat, Georg Hoefner, Klaus Wanner, Anna Wieckowska, Barbara Malawska
Summary: A highly selective hBuChE inhibitor (29) with potential benefits for treating Alzheimer's disease has been identified through extensive in vitro and in vivo evaluations.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Jiameng Li, Muya Xiong, Jiayuan Liu, Fengping Zhang, Minjun Li, Wenfeng Zhao, Yechun Xu
Summary: cGAS plays an important role in the inflammatory response and aberrant activation is associated with immune-mediated inflammatory disorders. Natural flavonoid compounds baicalein and baicalin have been found to inhibit cGAS activity and provide insight into their anti-inflammatory mechanism.
BIOORGANIC CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Modesto de Candia, Alexander A. Titov, Antonio Viayna, Larisa N. Kulikova, Rosa Purgatorio, Brigida Piergiovanni, Mauro Niso, Marco Catto, Leonid G. Voskressensky, F. Javier Luque, Cosimo D. Altomare
Summary: This study investigated the inhibitory activity of newly synthesized derivatives on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Compound 7c was found to be a highly potent and selective inhibitor of BChE, with a noncompetitive/mixed-type inhibition mechanism. The study also highlighted the structural factors that enhance inhibition potency and selectivity, as well as the differences between the binding sites of equine BChE and recombinant human BChE.
CHEMICO-BIOLOGICAL INTERACTIONS
(2023)
Article
Chemistry, Medicinal
Filip Pidany, Jana Kroustkova, Abdullah Al Mamun, Daniela Suchankova, Xavier Brazzolotto, Florian Nachon, Fabien Chantegreil, Rafael Dolezal, Lenka Pulkrabkova, Lubica Muckova, Martina Hrabinova, Vladimir Finger, Martin Kufa, Ondrej Soukup, Daniel Jun, Jaroslav Jenco, Jiri Kunes, Lucie Novakova, Jan Korabecny, Lucie Cahlikova
Summary: This study focuses on the design, synthesis, and in vitro evaluation of novel hBChE inhibitors for the treatment of late-stage AD. Compound 87 exhibits promising BChE inhibitory activity and low cytotoxicity, making it a potential lead compound for further development. Crystallographic and QSAR analyses provide insights into the binding mode and structure-activity relationship of these compounds.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Yasunobu Ushiki, Kenichi Kawabe, Kumiko Yamamoto-Okada, Fumito Uneuchi, Yuta Asanuma, Chitose Yamaguchi, Hiroshi Ohta, Tsuyoshi Shibata, Tomohiro Abe, Lisa Okumura-Kitajima, Yuki Kosai, Mayumi Endo, Katsumasa Otake, Eiji Munetomo, Teisuke Takahashi, Hiroyuki Kakinuma
Summary: This article reports the discovery of gut-selective NaPi2b inhibitors with good activity, low systemic exposure, and moderate hydrophobicity. These inhibitors have the potential to be candidate drugs for the treatment of hyperphosphatemia.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Jing Guo, Shuang Xiang, Jie Wang, Yang Zhou, Zuqin Wang, Zhang Zhang, Ke Ding, Xiaoyun Lu
Summary: Tropomyosin receptor kinases A (TrkA) is a potential therapeutic target for the treatment of tumors and chronic pain. This study discovered a novel TrkA allosteric inhibitor through structure-based virtual screening and conducted preliminary research on its properties.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Satoshi Inoue, Yoshinobu Yamane, Shuntaro Tsukamoto, Norio Murai, Hiroshi Azuma, Satoshi Nagao, Kyoko Nishibata, Sayo Fukushima, Kenji Ichikawa, Takayuki Nakagawa, Naoko Hata Sugi, Daisuke Ito, Yu Kato, Aya Goto, Dai Kakiuchi, Takashi Ueno, Junji Matsui, Tomohiro Matsushima
Summary: Novel 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine derivatives were designed and synthesized to evaluate their inhibitory activities on Axl and Mer, resulting in the identification of ER-001259851-000 as a potent and selective Axl inhibitor with drug-likeness and promising pharmacokinetic profile in mice.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Tao Liang, Junxin Xue, Zefu Yao, Yang Ye, Xinying Yang, Xuben Hou, Hao Fang
Summary: Compound 71, a new HDAC6 inhibitor, showed superior selectivity and activity, with potential application in cancer therapy.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Stane Pajk, Damijan Knez, Urban Kosak, Maja Zorovic, Xavier Brazzolotto, Nicolas Coquelle, Florian Nachon, Jacques-Philippe Colletier, Marko Zivin, Jure Stojan, Stanislav Gobec
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2020)
Article
Chemistry, Medicinal
Damijan Knez, Natalia Colettis, Luca G. Iacovino, Matej Sova, Anja Pislar, Janez Konc, Samo Lesnik, Josefina Higgs, Fabiola Kamecki, Irene Mangialavori, Ana Dolsak, Simon Zakelj, Jurij Trontelj, Janko Kos, Claudia Binda, Mariel Marder, Stanislav Gobec
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Multidisciplinary Sciences
Eugenio de la Mora, Nicolas Coquelle, Charles S. Bury, Martin Rosenthal, James M. Holton, Ian Carmichael, Elspeth F. Garman, Manfred Burghammer, Jacques-Philippe Colletier, Martin Weik
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2020)
Article
Chemistry, Multidisciplinary
Matej Sova, Rok Frlan, Stanislav Gobec, Zdenko Casar
Article
Chemistry, Medicinal
Elisabet Viayna, Nicolas Coquelle, Monika Cieslikiewicz-Bouet, Pedro Cisternas, Carolina A. Oliva, Elena Sanchez-Lopez, Miren Ettcheto, Manuela Bartolini, Angela De Simone, Mattia Ricchini, Marisa Rendina, Megane Pons, Omidreza Firuzi, Belen Perez, Luciano Saso, Vincenza Andrisano, Florian Nachon, Xavier Brazzolotto, Maria Luisa Garcia, Antoni Camins, Israel Silman, Ludovic Jean, Nibaldo C. Inestrosa, Jacques-Philippe Colletier, Pierre-Yves Renard, Diego Munoz-Torrero
Summary: By combining the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin, compounds with nanomolar potencies towards AChE and BChE were created, demonstrating potential therapeutic effects for Alzheimer's disease.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Lindsay McGregor, Tamas Foldes, Soi Bui, Martine Moulin, Nicolas Coquelle, Matthew P. Blakeley, Edina Rosta, Roberto A. Steiner
Summary: This study investigates the hydration step of urate oxidase reaction using high-resolution neutron/X-ray crystallographic analysis and molecular dynamics simulations. The catalytic water molecule W1 plays a crucial role in the reaction, stabilized by interactions with specific residues and the inhibitor. Conformational heterogeneity of Asn254 is proposed as an active mechanism to facilitate W1/O-2 exchange during catalysis.
Article
Multidisciplinary Sciences
D. Sorigue, K. Hadjidemetriou, S. Blangy, G. Gotthard, A. Bonvalet, N. Coquelle, P. Samire, A. Aleksandrov, L. Antonucci, A. Benachir, S. Boutet, M. Byrdin, M. Cammarata, S. Carbajo, S. Cuine, R. B. Doak, L. Foucar, A. Gorel, M. Grunbein, E. Hartmann, R. Hienerwadel, M. Hilpert, M. Kloos, T. J. Lane, B. Legeret, P. Legrand, Y. Li-Beisson, S. L. Y. Moulin, D. Nurizzo, G. Peltier, G. Schiro, R. L. Shoeman, M. Sliwa, X. Solinas, B. Zhuang, T. R. M. Barends, J-P Colletier, M. Joffre, A. Royant, C. Berthomieu, M. Weik, T. Domratcheva, K. Brettel, M. H. Vos, I Schlichting, P. Arnoux, P. Mueller, F. Beisson
Summary: The study found that Fatty Acid Photodecarboxylase (FAP) exhibits efficient decarboxylation activity, primarily achieved through the reduction of the flavin chromophore and direct removal of carbon dioxide by the substrate carboxyl group. Essential residues R451 and C432 are crucial for substrate stabilization and charge transfer.
Article
Biochemistry & Molecular Biology
Tjasa Mazej, Damijan Knez, Anze Meden, Stanislav Gobec, Matej Sova
Summary: The study successfully synthesized three dual-acting compounds inhibiting two enzymes related to the pathobiology of Alzheimer's disease by introducing a carbamate moiety on the structure of an in-house irreversible monoamine oxidase B (MAO-B) inhibitor, with compound 15 demonstrating the best balanced inhibition effect.
Article
Chemistry, Multidisciplinary
Vinardas Kelpsas, Octav Caldararu, Matthew P. Blakeley, Nicolas Coquelle, Rikkert K. Wierenga, Ulf Ryde, Claes von Wachenfeldt, Esko Oksanen
Summary: This study investigates the neutron structures of Leishmania mexicana TIM with inhibitors, revealing the protonation states of active-site residues. Quantum calculations were used to study the reaction mechanism based on the identified protonation states.
Article
Biochemistry & Molecular Biology
Katarina Grabrijan, Nika Strasek, Stanislav Gobec
Summary: Monocyclic ss-lactams have a wide range of biological activities, including antibacterial, anticancer, and cholesterol absorption inhibitory activities. This study presents an optimized synthesis method for orthogonally protected 3-amino-4-substituted monocyclic ss-lactams and investigates challenging deprotection methods. The results provide valuable insights into the synthesis and modification of monocyclic ss-lactams with potential pharmacological activities.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Bernarda Majc, Anamarija Habic, Metka Novak, Ana Rotter, Andrej Porcnik, Jernej Mlakar, Vera Zupunski, Ursa Pecar Fonovic, Damijan Knez, Nace Zidar, Stanislav Gobec, Janko Kos, Tamara Lah Turnsek, Anja Pislar, Barbara Breznik
Summary: This study found that cathepsin X is upregulated in human GBM tissues and localized in GBM cells, tumor-associated macrophages, and microglia. Selective cathepsin X inhibitors can decrease the viability of GBM cells and are colocalized with gamma-enolase, suggesting that cathepsin X is involved in GBM progression and could be a potential therapeutic target.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Levente Kollar, Martina Gobec, Matic Proj, Lara Smrdel, Damijan Knez, Timea Imre, Agnes Gomory, Laszlo Petri, Peter Abranyi-Balogh, Dorottya Csanyi, Gyoergy G. Ferenczy, Stanislav Gobec, Izidor Sosic, Gyoergy M. Keseru
Summary: Constitutive- and immunoproteasomes are vital components of the protein homeostasis system. Selective inhibition of immunoproteasomes shows promise for treating various diseases, and two series of compounds targeting proteasomes have been described in this study. The compounds exhibit significant inhibitory activities against specific subunits of the proteasomes, highlighting their potential for developing selective immunoproteasome inhibitors or compounds targeting multiple subunits.
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.